Steroids and methods of manufacture

ABSTRACT

Methods for producing enantiodefined polycyclic compounds, particularly tetracyclic compounds, are provided. More particularly, synthetic methods for producing biologically active enantiodefined steroidal compositions of both natural (“nat-”) and unnatural (“ent-”) absolute stereochemistry are provided. An exemplary method for manufacturing a tetracyclic compound comprises a step of forming a hydrindane intermediate through coupling of a suitably functionalized enyne with a suitably functionalized alkyne and subsequently performing an intramolecular ring-closing reaction to form the tetracyclic compound. Steroidal compounds obtained by this method and methods of using such steroidal compounds in human and/or animal therapeutics and medicines are also provided.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. Patent Application No.62/605,551, filed on Aug. 16, 2017, the entire contents of which ishereby incorporated by reference.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under R01 GM080266awarded by the National Institutes of Health. The government has certainrights in the invention.

FIELD OF THE INVENTION

The present disclosure relates to methods of producing enantiodefinedpolycyclic ring compounds through unique intermediates and synthesisstrategies. More particularly, the present disclosure provides syntheticmethods of producing biologically active enantiodefined steroidalcompositions of both natural and unnatural (“ent-”) absolutestereochemistry. The present disclosure also relates to methods of usingactive natural and ent-steroidal compositions prepared from this methodas biologically active (e.g., therapeutic) components in compositionsand/or directly as human and/or animal therapeutics and medicines. Thepresent disclosure further relates to methods of producing and usingnatural and ent-steroids in chemical, pharmacological, and biologicalstudies and research.

BACKGROUND OF THE INVENTION

Steroids, as a class of biomolecules, have been intensely studied sincethe first correct structural elucidation of a natural steroid and thesubsequent synthesis of equilenin in 1932 and 1939, respectively.Tremendous scientific effort has been expended to better understand thebiological and physiological roles played by the myriad of naturallyoccurring steroids as well as to isolate natural steroids and tosynthetically or semi-synthetically produce steroids and steroidalderivatives. Efforts in this area established a scientific foundationthat has delivered >100 FDA-approved steroidal agents as therapeutics,leading to their current status as arguably the most well-studied andsuccessful class of natural product-inspired pharmaceuticals.

Early scientific breakthroughs that established the steroidpharmaceutical industry were based on semisynthetic methods ofproduction, wherein, available naturally occurring steroids weresubsequently chemically transformed into high-value therapeutic agents.One such example, of a semisynthetic production pathway is the Merckbile acid-to-cortisone process. (See, Pines, S. H., Org. Proc. Res.Dev., 8, 708-724 [2004]). The resultant cortisone acetate produced viathe Merck process is functionally identical to naturally producedcortisone (17α,21-dihydroxypregn-4-ene-3,11,20-trione) resulting fromsteroidogenesis. As such, the Merck process-derived cortisone sharesboth the beneficial potent anti-inflammatory properties as well as thepotential deleterious systemic effects from long term use as naturallyproduced cortisone (e.g., hyperglycemia, insulin resistance, diabetesmellitus, osteoporosis, anxiety, depression, amenorrhoea, cataracts,Cushing's syndrome and glaucoma, and immune system suppression).Similarly, the testosterone, estrone, estradiol, progesterone, andcortisone steroids, produced using the Marker degradation, a syntheticroute developed by American chemist Russell Earl Marker, share the samebeneficial biological activities and potential side-effects with theirsteroidogenic cognates. (See, Marker, R. E., et al., J. Am. Chem. Soc.,62, 2525-2532 [1940]; Pines, S. H., Org. Proc. Res. Dev., 8, 708-724[2004]; and Renneberg, R., Biotechnol. J., 3, 449-451 [2008]). The Merckand Marker processes stand out as important semisynthetic routes toproducing valuable medicinal products.

In addition to the aforementioned semisynthetic routes to steroidproduction, there are a number of examples of de novo synthetic pathwaysfor producing synthetic steroids starting from non-steroidal materials,notably the Smith-Torgov synthesis of estranes and biomimeticcation-olefin cyclization processes, among others. Semi-syntheses,nevertheless, remains the primary means by which pharmaceuticallyrelevant steroids are prepared.

The aforementioned, and other presently available synthetic andsemisynthetic routes to steroid production are, in summation, oftencomplex, inefficient, and/or wholly incapable of producing advantageouscollections (i.e., libraries) of highly oxygenated/functionalizedsteroidal target compositions necessary for advancement through moderndrug development. Steroids have had a transformative impact on medicineand society, playing vital roles as oral contraceptives, treatments forcancer (including anti-angiogenic agents), heart failure, inflammation,pain, and traumatic brain injuries, among others, and as import chemicalprecursors for numerous steroid derivatives. Despite these manyadvances, substantial barriers persist that greatly limit the types ofsteroidal compositions that can efficiently be prepared and explored aspotential medicines and biological tools/probes.

While semisynthetic routes to steroids (those beginning with a readilyavailable natural steroid) have been incredibly powerful, they are notsuitable for producing non-naturally occurring “ent-steroids” (definedby an unnatural absolute stereochemistry of the tetracycle). This pointdeserves further consideration, as diligent advancement of the newmethods related to steroid synthesis have overtime positioned steroidalcompositions as a “privileged” class of molecules (i.e., pharmacophores)within the pharmaceutical industry. While pairs of enantiomers shareidentical physical properties, and in the case of steroids “drug-like”properties, it is surprising that 100% of currently FDA-approvedsteroidal drugs are of the natural (‘nat’) antipode. As compared tonatural steroids (“nat-steroids”), synthetic ent-steroidal compositionshave complementary three dimensional structures while offering similar“drug-like” properties. As a result synthetic ent-steroids areprivileged natural product-inspired scaffolds of great potentialtherapeutic relevance, and are distinct compositions in comparison totheir natural isomers. (See, Akwa, Y., et al., Proc. Natl. Acad. Sci.U.S.A., 98, 14033-14037 [2001]; Green, P. S., et al., Endocrinology,142, 400-406 [2001]; Biellmann, J. F., Chem. Rev., 103, 2019-2033[2003]; Covey, D. F., Steroids, 74(7):577-585 [2009]; and Petit, G. H.,et al., Eur. Neuropsychopharmacol., 21, 211-215 [2011]). In summary,ent-steroids are an important class of privileged pharmaceuticaldrug-like molecules that presently cannot be fully leveraged inbiological and pharmaceutical research efforts because these moleculesare not readily available from natural sources and existing chemicalsynthesis pathways are inefficient and not flexible enough to producediverse collections of steroids suitable for drug discovery anddevelopment.

A practical method for efficient and stereospecific production ofent-steroids would enable scientists and physicians to better exploitthe as yet untapped potential of ent-steroids as useful tools andtherapeutics. Accordingly, what is needed are efficient andstep-economical (i.e., concise), flexible, convergent, andenantiospecific methods of synthesizing synthetic nat- and/orent-steroids having varying stereochemistry and substitution, and/orsuitability for subsequent functionalization processes (i.e.,manipulation of functionality in each ring of the characteristictetracyclic nucleus) at research and/or production scale.

SUMMARY OF THE INVENTION

The present disclosure relates to methods of producing enantiodefinedpolycyclic ring compounds. More particularly, the present disclosureprovides synthetic methods of producing biologically active steroidalcompositions of both natural and unnatural absolute stereochemistry(nat- and ent-).

The present disclosure also relates to enantiodefined tetracycliccompounds (e.g., steroidal tetracycles) obtainable by or accessible fromthe methods described herein.

The present disclosure also relates to methods of using tetracycliccompounds, including natural and ent-steroidal compounds that areaccessible from this method, as biologically active (e.g., therapeutic)components in compositions and/or directly as human and/or animaltherapeutics and medicines. The present disclosure further relates tomethods of producing and using natural and ent-steroids in chemical,pharmacological, and biological studies and research.

The present disclosure relates to tetracyclic steroidal compounds havinga structure corresponding to Formula (IA), Formula (IB), Formula (IC),or Formula (ID):

wherein the variables (R groups) are defined herein.

The present disclosure also relates to methods for making suchcompounds, pharmaceutical compositions containing such compounds, andmethod for using such compounds and compositions to, for example, treatproliferative disease such as cancer or neurodegenerative diseases.

The present disclosure also relates to intermediate compounds useful formaking tetracyclic steroidal compounds disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying Figures of which:

FIG. 1 shows a generalized chemical pathway useful for generating a widerange of steroidal systems in a concise and enantiospecific manner.

FIG. 2 shows the mechanistic divergence in the vinylcyclopropanerearrangement and intramolecular Friedel-Crafts alkylation process,wherein, formation of C—C bonds is depicted in intermediate (III)between C5-C6; in intermediate (IV) between C5-C6; in intermediate (F)between C5-C6; and in intermediate (G) between C5-C6 and C9-C10,respectively.

FIG. 2 shows the mechanistic rationale for divergence in thevinylcyclopropane rearrangement and intramolecular Friedel-Craftsalkylation process, wherein reaction by way of intermediate III does notproceed by rearrangement after C5-C6 bond-formation, and reaction by wayof intermediate IV proceeds by an alkyl shift after formation of theC5-C6 bond.

FIG. 3A shows production of several exemplary steroids with varyingsubstitution and stereochemistry (e.g., steroidal compounds 34-41).

FIG. 3B shows a multigram-scale preparation of a synthetic ent-steroid(steroid ent-12).

FIG. 3C shows the preparation ofent-estra-1,3,5(10),6,8-pentaene-3,16α-diol.

FIG. 3D shows an ent-steroid with cytotoxic properties wherein cellswere plated at 1000 cells/well of a 96 well plate. The following day,ent-steroidal compound 39 was added in 2-fold dilutions (8wells/concentration). After 7 days growth, cells were lysed and analyzedfor total DNA content as described in Montano et al. (See, Montano, R.,et al., Mol. Cancer Therap., 11:427-438 [2012]).

DETAILED DESCRIPTION OF THE INVENTION

This detailed description is intended only to acquaint others skilled inthe art with the present invention, its principles, and its practicalapplication so that others skilled in the art may adapt and apply theinvention in its numerous forms, as they may be best suited to therequirements of a particular use. This description and its specificexamples are intended for purposes of illustration only. This invention,therefore, is not limited to the embodiments described in this patentapplication, and may be variously modified.

A. DEFINITIONS

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.That the present disclosure may be more readily understood, select termsare defined below

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, up to 10%, up to 5%, or up to 1% of a given value.Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, preferablywithin 5-fold, and more preferably within 2-fold, of a value. Whereparticular values are described in the application and claims, unlessotherwise stated the term “about” meaning within an acceptable errorrange for the particular value should be assumed.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function and/or a targetprotein. Preferred agonists herein specifically interact with (e.g.,bind to) their target(s).

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction and/or a target protein. Preferred antagonists/inhibitorsherein specifically interact with (e.g., bind to) their target(s).

The term “antiangiogenic” refers to the ability to inhibit or impair theformation of blood vessels, including but not limited to inhibitingendothelial cell proliferation, endothelial cell migration, andcapillary tube formation.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The terms “co-administration,” “administered in combination with,” andtheir grammatical equivalents, encompass administration of two or moreagents to a subject so that both agents and/or their metabolites arepresent in the subject at the same time. Co-administration includessimultaneous administration in separate compositions, administration atdifferent times in separate compositions, or administration in acomposition in which both agents are present. Co-administered agents maybe in the same formulation. Co-administered agents may also be indifferent formulations.

The term “in vivo” refers to an event that takes place in a subject'sbody. The term “in vitro” refers to an event that takes places outsideof a subject's body. For example, an in vitro assay encompasses anyassay run outside of a subject assay. In vitro assays encompasscell-based assays in which cells alive or dead are employed. In vitroassays also encompass cell-free assays in which no intact cells areemployed.

The term “neoplastic condition” refers to the presence of cellspossessing abnormal growth characteristics, such as uncontrolledproliferation, immortality, metastatic potential, rapid growth andproliferation rate, perturbed oncogenic signaling, and certaincharacteristic morphological features. This includes but is not limitedto the growth of benign or malignant cells (e.g., tumor cells),including such growth that correlates with overexpression of a tyrosineor serine/threonine kinase.

The term “pharmaceutically acceptable” is used adjectivally to mean thatthe modified noun is appropriate for use as a pharmaceutical product oras a part of a pharmaceutical product. The phrase “pharmaceuticallyacceptable” further denotes those compounds, materials, compositions,and/or dosage forms which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of human beingsand animals without excessive toxicity, irritation, allergic response,or other problem or complication commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

The terms “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” include any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions of theinvention is contemplated. Supplementary active ingredients can also beincorporated into the compositions.

The terms “prevent”, “preventing” and “prevention” (i) refer to a methodfor preventing the onset of a condition, disorder, or disease and/or theattendant symptoms thereof or barring a subject from acquiring acondition, disorder, or disease and/or (ii) refer to an approach forobtaining beneficial or desired results including but not limited toprophylactic benefit. As used herein, “prevent”, “preventing” and“prevention” also include delaying the onset of a condition, disorder,or disease and/or the attendant symptoms thereof and reducing asubject's risk of acquiring a condition, disorder, or disease. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

The term “prophylactic effect” includes delaying or eliminating theappearance of a disease or condition, delaying or eliminating the onsetof symptoms of a disease or condition, slowing, halting, or reversingthe progression of a disease or condition, or any combination thereof.

The term “steroid” refers to a compound having carbon atoms arranged ina 4-ring structure. (See, e.g., J. American Chemical Society,82:5525-5581 (1960); and, Pure and Applied Chemistry, 31:285-322(1972)).

The term “subject” refers to an animal, such as a mammal, for example ahuman or other primate. The methods described herein can be useful inboth human therapeutics, pre-clinical, and veterinary applications. Insome embodiments, the subject is a mammal, and in some embodiments, thesubject is human.

A “sub-therapeutic amount” of an agent or therapy is an amount less thanthe effective amount for that agent or therapy, but when combined withan effective or sub-therapeutic amount of another agent or therapy canproduce a result desired by the physician, due to, for example, synergyin the resulting efficacious effects, or reduced side effects.

A “synergistically effective” therapeutic amount or “synergisticallyeffective” amount of an agent or therapy is an amount which, whencombined with an effective or sub-therapeutic amount of another agent ortherapy, produces a greater effect than when either of the two agentsare used alone. In some embodiments, a synergistically effectivetherapeutic amount of an agent or therapy produces a greater effect whenused in combination than the additive effects of each of the two agentsor therapies when used alone. The term “greater effect” encompasses notonly a reduction in symptoms of the disorder to be treated, but also animproved side effect profile, improved tolerability, improved patientcompliance, improved efficacy, or any other improved clinical outcome.

The term “therapeutic effect” encompasses a therapeutic benefit and/or aprophylactic benefit as described herein.

The term “therapeutically effective amount” refers to a sufficientamount of the compound to treat a condition, disorder, or disease, at areasonable benefit/risk ratio applicable to any medical treatment. Whenused in a medical treatment, a therapeutically effective amount of oneof the present compounds can be employed in pure form or, where suchforms exist, in pharmaceutically acceptable salt or ester, or amideform. Alternatively, the compound can be administered as apharmaceutical composition containing the compound of interest incombination with one or more pharmaceutically acceptable carriers.

The terms “treatment”, “treating”, “palliating” and “ameliorating” areused interchangeably as context indicates. In particular, these terms(i) refer to a method for alleviating or abrogating a condition,disorder, or disease and/or the attendant symptoms thereof and/or (ii)refer to an approach for obtaining beneficial or desired resultsincluding but not limited to therapeutic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated. Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient may still be afflicted withthe underlying disorder.

The term “hydrocarbyl” or “hydrocarbon” refers to moieties consistingexclusively of the elements carbon and hydrogen, in a straight orbranched chain, or alternatively a cyclic structure, which mayoptionally be substituted with other hydrocarbon, halo (e.g., chlorine,fluorine, bromine) or hetero (e.g., oxygen, sulfur) substituents. Thesemoieties include alkyl, alkenyl, alkynyl and aryl moieties as well asalkyl, alkenyl, alkynyl and aryl moieties substituted with otheraliphatic or cyclic hydrocarbon groups such as, for example, alkaryl,alkenaryl and alkynaryl. In some instances, the number of carbon atomsin a hydrocarbon substituent (e.g., alkyl, alkenyl, alkynyl, orcycloalkyl) is indicated by the prefix “C_(x)-C_(y)-”, wherein x is theminimum and y is the maximum number of carbon atoms in the substituent.Thus, for example, “C₁-C₆-alkyl” refers to an alkyl substituentcontaining from 1 to 6 carbon atoms.

The term “substituted” is intended to indicate that one or morehydrogens on the substituent indicated in the expression using“substituted” is replaced with another group(s), provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. If a particular substituentis described as being “substituted”, it means that there are one or moresubstituents other than hydrogen attached to that particularsubstituent. Thus, for example, a substituted alkyl is an alkyl in whichat least one non-hydrogen substituent is in the place of a hydrogen atomon the alkyl. If a particular substituent is described as being“optionally substituted”, that particular substituent may be either (1)not substituted or (2) substituted. Combinations of variables orsubstituents are permissible only if such combinations result in stablecompounds. Stable compounds are compounds that can be isolated from areaction mixture.

“Acyl” refers an “R” group appended to the parent molecular moietythrough a carbonyl group and includes the groups (alkyl)-C(O)—,(aryl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality. In some embodiments, it isa C₁-C₁₀ acyl radical which refers to the total number of chain or ringatoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of theacyl group plus the carbonyl carbon of acyl, i.e., three other ring orchain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₄alkyl group. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl,decyl, and the like. The alkyl is attached to the rest of the moleculeby a single bond, for example, methyl (Me), ethyl (Et), n-propyl,1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

The term “lower alkyl” or “C₁-C₆-alkyl” means a straight or branchedhydrocarbon chain containing from 1 to 6 carbon atoms.

The terms “alkene” or “alkenyl” refer to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing at least one carbon-carbon double bond, and havingfrom two to ten carbon atoms (i.e., C₂-C₁₀ alkenyl). In certainembodiments, an alkenyl comprises two to eight carbon atoms. In otherembodiments, an alkenyl comprises two to five carbon atoms (e.g., C₂-C₅alkenyl). The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

The term “alkyne” or “alkynyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing at least one carbon-carbon triple bond, having fromtwo to ten carbon atoms (i.e., C₂-C₁₀ alkynyl). In other embodiments, analkynyl has two to five carbon atoms (e.g., C₂-C₅ alkynyl). The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8carbon atoms of a straight, branched, cyclic configuration andcombinations thereof attached to the parent structure through an oxygen.Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like. “Lower alkoxy” refers to alkoxy groupscontaining one to six carbons. In some embodiments, C₁-C₄ alkyl, is analkyl group which encompasses both straight and branched chain alkyls offrom 1 to 4 carbon atoms.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R)₂or —NHC(O)R, where R is selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), each of which moiety mayitself be optionally substituted. In some embodiments it is a C₁-C₄amido or amide radical, which includes the amide carbonyl in the totalnumber of carbons in the radical. The R² of —N(R)₂ of the amide mayoptionally be taken together with the nitrogen to which it is attachedto form a 4-, 5-, 6-, or 7-membered ring. An amide may be an amino acidor a peptide molecule attached to a compound of Formula (I), therebyforming a prodrug. Any amine, hydroxy, or carboxyl side chain on thecompounds described herein can be amidified. The procedures and specificgroups to make such amides are known to those of skill in the art andcan readily be found in reference sources such as Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, NewYork, N.Y., 1999, which is incorporated herein by reference in itsentirety.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless statedotherwise specifically in the specification. When a —N(R^(a))₂ group hastwo R^(a) other than hydrogen they can be combined with the nitrogenatom to form a 4-, 5-, 6-, or 7-membered ring. For example, —N(R^(a))₂is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl.

The terms “aromatic” or “aryl” refer to an aromatic radical with six tofourteen ring atoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has atleast one ring having a conjugated pi electron system which iscarbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicalsformed from substituted benzene derivatives and having the free valencesat ring atoms are named as substituted phenylene radicals. Bivalentradicals derived from univalent polycyclic hydrocarbon radicals whosenames end in “-yl” by removal of one hydrogen atom from the carbon atomwith the free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. In the case of a polycyclic aryl, only one ring of thepolycyclic system is required to be aromatic while the remaining ring(s)may be saturated, partially saturated or unsaturated. Representativeexamples of aryl include, but are not limited to, phenyl, naphthalenyl,indenyl, indanyl, and tetrahydronapthyl.

The terms “aryl-alkyl”, “arylalkyl” and “aralkyl” refers to an arylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Examples of aryl-alkylgroups include, but are not limited to, optionally substituted benzyl,phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl,2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl,2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl,2-(2-methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl,2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl,3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2-methylphenyl)propyl,3-(4-methoxyphenyl)propyl, 3-(4-(trifluoromethyl)phenyl)propyl,3-(2,4-dichlorophenyl)propyl, 4-phenylbutyl, 4-(4-chlorophenyl)butyl,4-(2-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl,4-(2-methoxyphenyl)butyl, and 10-phenyldecyl. Either portion of themoiety is unsubstituted or substituted.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated, and contains from 3 to 14 carbon ring atoms. A cycloalkylmay be a single carbon ring, which typically contains from 3 to 8 carbonring atoms and more typically from 3 to 6 ring atoms. Examples ofsingle-ring cycloalkyls include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloseptyl, cyclooctyl, cyclononyl, and cyclodecyl. A cycloalkyl mayalternatively be polycyclic or contain more than one ring. Examples ofpolycyclic cycloalkyls include bridged, fused, and spirocycliccarbocyclyls (e.g., norbornyl).

The term “bicycloalkyl” refers to a structure consisting of twocycloalkyl moieties, unsubstituted or substituted, that have two or moreatoms in common. If the cycloalkyl moieties have exactly two atoms incommon they are said to be “fused”. Examples include, but are notlimited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If thecycloalkyl moieties have more than two atoms in common they are said tobe “bridged.” Examples include, but are not limited to,bicyclo[3.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

The term “cycloalkenyl” refers to a cyclic aliphatic 3 to 8 memberedring structure, optionally substituted with alkyl, hydroxy and halo,having 1 or 2 ethylenic bonds such as methylcyclopropenyl,trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl,1,4-cyclohexadienyl, and the like.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-fluoroethyl, 2-bromoethyl,3-iodopropyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, 2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl, perfluoropropyl, 8-chlorononyl, and the like.

The term “haloalkenyl” refers to an alkenyl group substituted with oneor more halo groups (one or more hydrogen atoms of the alkenyl group arereplaced by a halogen atom).

The term “haloalkynyl” refers to an alkynyl group substituted with oneor more independent halo groups (one or more hydrogen atoms of thealkynyl group are replaced by a halogen atom).

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halo groups, for example chloromethoxy, trifluoromethoxy,difluoromethoxy, perfluoroisobutoxy, and the like.

The term “heteroatom” or “ring heteroatom” includes oxygen (O), nitrogen(N), sulfur (S), phosphorus (P), and silicon (Si) and, preferably oxygen(O), nitrogen (N), or sulfur (S).

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals and whichhave one or more skeletal chain atoms selected from an atom other thancarbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinationsthereof. A numerical range may be given, e.g., C₁-C₄ heteroalkyl whichrefers to the chain length in total, which in this example is 1 to 4atoms long or a 5- to 14-membered heteroaryl ring which refers to thenumber of ring atoms, which in this example is 5 to 14 ring atoms. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the rest of the molecule may be througheither a heteroatom or a carbon in the heteroalkyl chain.

The terms “heteroaryl” or “heteroaromatic” refer to a 5- to 18-memberedaromatic radical (e.g., 5- to 14-membered heteroaryl) that includes oneor more ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range; e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. Bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical, e.g., a pyridyl group with two points of attachment is apyridylidene. A heteroaryl may be monocyclic or polycyclic (i.e., maycontain more than one ring). In the case of a polycyclic heteroaryl,only one ring of the polycyclic system is required to be aromatic whilethe remaining ring(s) may be saturated, partially saturated orunsaturated. The polycyclic heteroaryl group may be fused or non-fused.An N-containing “heteroaromatic” or “heteroaryl” moiety refers to anaromatic group in which at least one of the skeletal atoms of the ringis a nitrogen atom. The heteroatom(s) in the heteroaryl radical isoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl is attached to the rest of themolecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,benzothiazolyl, benzothienyl (benzothiophenyl),benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl).

The terms “heteroarylalkyl”, “heteroarylalkyl”, “heteroaryl-alkyl”,“heteroaryl-alkyl”, “hetaralkyl” and “heteroaralkyl” are used todescribe a heteroaryl group, as defined herein, appended to the parentmolecular moiety through an alkylene group, as defined herein. Thealkylene chain can be branched or straight chain forming a linkingportion of the heteroaralkyl moiety with the terminal heteroarylportion, as defined above, for example 3-furylmethyl, thenyl, furfuryl,and the like. Either portion of the moiety is unsubstituted orsubstituted.

The term “heterocycloalkyl” refers to a stable 3- to 18-memberednon-aromatic ring radical that comprises at least one ring heteroatomselected from nitrogen, oxygen and sulfur. Whenever it appears herein, anumerical range such as “3 to 18” refers to each integer in the givenrange; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl groupmay consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18ring atoms. In some embodiments, it is a 5- to 10-memberedheterocycloalkyl. In some embodiments, it is a 4- to 10-memberedheterocycloalkyl. In some embodiments, it is a 3- to 10-memberedheterocycloalkyl. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. The heteroatoms in the heterocycloalkyl radical may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocycloalkyl radical is partially orfully saturated. The heterocycloalkyl may be attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. “Heterocycloalkyl” also includes bicyclicring systems wherein one non-aromatic ring, usually with 3 to 7 ringatoms, contains at least 2 carbon atoms in addition to 1-3 heteroatomsindependently selected from oxygen, sulfur, and nitrogen, as well ascombinations comprising at least one of the foregoing heteroatoms; andthe other ring, usually with 3 to 7 ring atoms, optionally contains 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen andis not aromatic.

The term “oxo” refers to an oxygen that is double bonded to a carbonatom. One in the art understands that an “oxo” requires a second bondfrom the atom to which the oxo is attached. Accordingly, it isunderstood that oxo cannot be substituted onto an aryl or heteroarylring, unless it forms part of the aromatic system as a tautomer.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present disclosure shall have the meanings that arecommonly understood by those of ordinary skill in the art. The meaningand scope of the terms should be clear, however, in the event of anylatent ambiguity, definitions provided herein take precedent over anydictionary or extrinsic definition.

Further, unless otherwise required by context, singular terms shallinclude pluralities and plural terms shall include the singular. Forexample, the singular forms “a”, “an” and “the” are intended to includethe plural forms as well, unless the context clearly indicatesotherwise.

In this application, the use of “or” means “and/or” unless statedotherwise. Furthermore, the use of the term “including”, as well asother forms, such as “includes” and “included”, is not limiting.Furthermore, to the extent that the terms “including”, “includes”,“having”, “has”, “with”, or variants thereof are used in either thedetailed description and/or the claims, such terms are intended to beinclusive in a manner similar to the term “comprising.”

In certain aspects, the present disclosure relates to compounds (andmethods of making such compounds, compositions comprising suchcompounds, and methods of using such compounds) comprising a generaltetracyclic steroidal (A, B, C, D) ring structure, as follows:

The numbering convention throughout the present disclosure is inaccordance with numbered structure above.

In reference to the general tetracyclic steroidal (A, B, C, D) ringstructure, it will be well appreciated that in view of the disclosurecontained herein as well as the teachings in the relevant fields of art,the compounds, compositions, and methods of the present disclosure arenot limited to any particular respective constituent (R) group(s) at thevarious numbered carbon atoms in the general tetracyclic steroidal (A,B, C, D) ring structure. Moreover, it will be well appreciated that inview of the disclosure contained herein as well as the teachings in therelevant fields of art, the compounds, compositions, and methods of thepresent disclosure may comprise ones in which the A ring of the generaltetracyclic steroidal (A, B, C, D) ring structure can be saturated,partially unsaturated, or completely unsaturated; likewise, the B ringof the general tetracyclic steroidal (A, B, C, D) ring structure can besaturated, partially unsaturated, or completely unsaturated.

In some exemplary embodiments of the general tetracyclic steroidal (A,B, C, D) ring structure, each numbered carbon atom contains one or moresubstituents (as the rules of valency allow), wherein each substituentis independently selected from the group consisting of hydrogen; C₁-C₄alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; —CF₃; halo; ═O; —OH;—O—(C₁-C₄-alkyl); —OCH₂F; —OCHF₃; —OCF₃; —OC(O)—(C₁-C₄-alkyl);—OC(O)—(C₁-C₄-alkyl); —OC(O)NH—(C₁-C₄-alkyl); —OC(O)N(C₁-C₄-alkyl)₂;—OC(S)NH—(C₁-C₄-alkyl); —OC(S)N(C₁-C₄-alkyl)₂; —SH; —S—(C₁-C₄-alkyl);—S(O)—(C₁-C₄-alkyl); —S(O)₂—(C₁-C₄-alkyl); —SC(O)—(C₁-C₄-alkyl);—SC(O)O—(C₁-C₄-alkyl); —NH₂; —N(H)—(C₁-C₄-alkyl); —N(C₁-C₄-alkyl)₂;—N(H)C(O)—(C₁-C₄-alkyl); —N(CH₃)C(O)—(C₁-C₄-alkyl); —N(H)C(O)—CF₃;—N(CH₃)C(O)—CF₃; —N(H)C(S)—(C₁-C₄-alkyl); —N(CH₃)C(S)—(C₁-C₄-alkyl);—N(H)S(O)₂—(C₁-C₄-alkyl); —N(H)C(O)NH₂; —N(H)C(O)NH—(C₁-C₄-alkyl);—N(CH₃)C(O)NH—(C₁-C₄-alkyl); —N(H)C(O)N(C₁-C₄-alkyl)₂;—N(CH₃)C(O)N(C₁-C₄-alkyl)₂; —N(H)S(O)₂NH₂; —N(H)S(O)₂NH—(C₁-C₄-alkyl);—N(CH₃)S(O)₂NH—(C₁-C₄-alkyl); —N(H)S(O)₂N(C₁-C₄-alkyl)₂;—N(CH₃)S(O)₂N(C₁-C₄-alkyl)₂; —N(H)C(O)O—(C₁-C₄-alkyl);—N(CH₃)C(O)O—(C₁-C₄-alkyl); —N(H)S(O)₂O—(C₁-C₄-alkyl);—N(CH₃)S(O)₂O—(C₁-C₄-alkyl); —N(CH₃)C(S)NH—(C₁-C₄-alkyl);—N(CH₃)C(S)N(C₁-C₄-alkyl)₂; —N(CH₃)C(S)O—(C₁-C₄-alkyl); —N(H)C(S)NH₂;—NO₂; —CO₂H; —CO₂—(C₁-C₄-alkyl); —C(O)N(H)OH; —C(O)N(CH₃)OH:—C(O)N(CH₃)OH; —C(O)N(CH₃)O—(C₁-C₄-alkyl); —C(O)N(H)—(C₁-C₄-alkyl);—C(O)N(C₁-C₄-alkyl)₂; —C(S)N(H)—(C₁-C₄-alkyl); —C(S)N(C₁-C₄-alkyl)₂;—C(NH)N(H)—(C₁-C₄-alkyl); —C(NH)N(C₁-C₄-alkyl)₂;—C(NCH₃)N(H)—(C₁-C₄-alkyl); —C(NCH₃)N(C₁-C₄-alkyl)₂;—C(O)—(C₁-C₄-alkyl); —C(NH)—(C₁-C₄-alkyl); —C(NCH₃)—(C₁-C₄-alkyl);—C(NOH)—(C₁-C₄-alkyl); —C(NOCH₃)—(C₁-C₄-alkyl); —CN; —CHO; —CH₂OH;—CH₂O—(C₁-C₄-alkyl); —CH₂NH₂; —CH₂N(H)—(C₁-C₄-alkyl);—CH₂N(C₁-C₄-alkyl)₂; C₆-C₁₄-aryl; 5- to 14-membered heteroaryl;C₃-C₁₄-cycloalkyl; and 5- to 14-membered heterocyclyl.

In certain embodiments, unless otherwise stated or indicated by context,a substituent of the general tetracyclic steroidal (A, B, C, D) ringstructure, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, orheteroaryl, is optionally substituted with one or more of substituentswhich independently are: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —PO₃(R^(a))₂ whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

It is to be noted that the present disclosure encompasses a number ofcompounds having one or more chiral centers therein. Generally speaking,therefore, it is to be understood that the configuration at one or moreof these chiral centers may change without departing from the scope ofthe intended invention; that is, it is to be understood that the presentdisclosure extends to compounds specifically or generally describedherein as well as all related diastereomers and enantiomers.

In certain aspects, the present disclosure provides methods forsynthetic production of tetracyclic compositions comprising nat- as wellent-steroidal core chemical structures.

In certain embodiments, a group of the compositions of the presentdisclosure comprise the nat-steroidal structure of Formula (nat) or theent-steroidal structure of Formula (ent):

B. SYNTHETIC METHODS AND INTERMEDIATE COMPOUNDS

In one aspect, the present disclosure provides a method formanufacturing a tetracyclic compound, such as a compound having thegeneral tetracyclic steroidal (A, B, C, D) ring structure describedherein.

In certain embodiments, the method comprises a step of forming ahydrindane of Formula (Ei) as an intermediate through coupling of asuitably functionalized enyne (Ci) with a suitably functionalized alkyne(Di). Scheme 3b depicts an exemplary reaction for forming theintermediate hydrindane of Formula (Ei).

In Scheme 3b, a compound of Formula Ci is reacted with a compound ofFormula Di to give a hydrindane of Formula Ei.

With respect to a compound of Formula Ci (and, where applicable, theproduct of the reaction, a hydrindane of Formula Ei), LG is a leavinggroup; each R¹⁷ is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen, or two R^(17A) together form an oxo; and m is an integerselected from 0, 1, and 2; R¹³ is selected from the group consisting ofC₁₋₆-alkyl and C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl isoptionally substituted one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl,or C₁₋₆-alkoxy; wherein any C₃₋₈-cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀-aryl or 5- to 10-membered heteroaryl isoptionally substituted with one or more halogen, C₁₋₆-alkyl,C₁₋₆-haloalkyl, or C₁₋₆-alkoxy. Exemplary leaving groups include, butare not limited to, halogen, —O—Ar¹, where Ar¹ is a substituted orunsubstituted C₆₋₁₀-aryl or 5- to 10-membered heteroaryl, in particularO-phenyl, and —OSO₂R^(1a), wherein R^(1a) is aryl, such as p-tolyl orphenyl; alkyl such as methyl or ethyl; fluoroalkyl such astrifluoromethyl, perfluorobutyl (C₄F₉), perfluoropentyl, perfluorohexyl,and perfluorooctyl; -fluoroalkyl-O-fluoroalkyl such asperfluoroethoxyethyl; —N(alkyl)₂; fluoro; or imidazolyl.

With respect to a compound of Formula Di (and the product of thereaction, a hydrindane of Formula Ei), Cy is C₃₋₈-cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀-aryl, or 5- to 10-memberedheteroaryl; each R^(M) is independently selected from the groupconsisting of hydrogen, C₁₋₆-alkyl, trimethylsilyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, arylalkyl, and —OR^(MX), wherein R^(MX) ishydrogen, C₁₋₆-alkyl, or C₆₋₁₀-aryl; R^(A) is selected from the groupconsisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, hydroxy, —OR^(AX), —SR^(AY),—S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2),—N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to10-membered heteroaryl, or two R^(A) together form an oxo, whereinR^(AX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,—C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, —S(O)₂R^(Z1),C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl, R^(AY) is hydrogen,C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,—C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5-to 10-membered heteroaryl, wherein each of R^(Z1) and R^(Z2) areindependently hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, orC₁₋₆-alkoxy; and n is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; wherein any C₃₋₈-cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀-aryl or 5- to 10-membered heteroarylis optionally substituted with one or more halogen, C₁₋₆-alkyl,C₁₋₆-haloalkyl, or C₁₋₆-alkoxy.

In certain embodiments, the method further comprises a step (e.g., step(b)) of treating the hydrindane of Formula Ei to install a C6 carbon andprovide a reactive intermediate for B-ring formation.

In certain embodiments, the method further comprises a step (e.g., step(c)) of performing an intramolecular ring-closing reaction to form thetetracyclic compound.

In certain embodiments, step (b) comprises cyclopropanation of thecompound of Formula Ei to form a compound of Formula (Fi):

whereinX¹ and X² are independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,halogen, oxygen, —OR^(BX), —SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1),—S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2),—N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₆₋₁₀-aryl-C₁₋₆-alkyl, C₆₋₁₀-aryl-C₂₋₆-alkenyl, andC₆₋₁₀-aryl-C₂₋₆-alkynyl; and R^(DX) is hydrogen or an oxygen protectinggroup. In some such embodiments, the cyclopropanation reaction occurs inan organic solvent, such as a halogenated organic solvent (e.g., CHBr₃).In some such embodiments, the cyclopropanation reaction occurs in thepresence of a base, such as an alkali metal hydroxide (e.g., KOH). Insome such embodiments, the cyclopropanation reaction occurs in thepresence of a phase transfer catalyst, such as a quaternary ammoniumsalt, particularly trialkylbenzyl and tetraalkyl ammonium halides (e.g.,benzyltriethylammonium chloride). In certain embodiments, X¹ is halogen,preferably bromo. In certain embodiments, X² is halogen, preferablybromo. In some such embodiments, X¹ and X² are both halogen. In somesuch embodiments, X¹ and X² are both bromo. In certain embodiments,R^(DZ) is hydrogen. In certain embodiments, R^(DZ) is an oxygenprotecting group. Exemplary oxygen protecting groups include, but arenot limited to, methyl, tert-butyloxycarbonyl (BOC), methoxymethyl(MOM), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS),and tribenzylsilyl. Oxygen protecting groups are well known in the artand include those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley &Sons, 1999, incorporated herein by reference. In some such embodiments,higher yields may be encountered if protection of the secondary alcohol(at C16) is conducted prior to cyclopropanation.

In certain embodiments, step (b) further comprises treatment of thecompound of Formula Fi with an acid, such as TiCl₄, SnCl₄, BF₃OEt₂,preferably TiCl₄, in an organic solvent, such as dichloromethane,chlorobenzene, ethylenechloride, 1,2-dichlorobenzene, nitromethane,tetrachlorethane, or mixtures thereof, preferably nitromethane,optionally in the presence of a protic additive (i.e. methanol, ethanol,isopropanol). In certain embodiments, the reaction occurs under an inertatmosphere, such as N₂.

In certain embodiments, step (b) comprises an intramolecularFriedel-Crafts alkylation reaction.

In certain embodiments, the method comprises a step of forming thecompound of Formula (Ci). Schemes 3a and 3a′ depict exemplary reactionsfor forming a the compound of Formula (Ci).

In Scheme 3a, a compound of Formula (Ai) is reacted with a compound ofFormula (Bi) to give a compound of Formula (Ci).

In Scheme 3a′, a compound of Formula (A′i) is reacted with a compound ofFormula (B′i) to give a compound of Formula (C′i).

With respect to a compound of Formula (Ai) (and the product of thereaction, a compound of Formula (Ci)), LG is a leaving group. Exemplaryleaving groups include, but are not limited to, halogen, —O—Ar¹, whereAr¹ is a substituted or unsubstituted C₆₋₁₀-aryl or 5- to 10-memberedheteroaryl, in particular —O-phenyl, and —OSO₂R^(1a), wherein R^(1a) isaryl, such as p-tolyl or phenyl; alkyl such as methyl or ethyl;fluoroalkyl such as trifluoromethyl, perfluorobutyl (C₄F₉),perfluoropentyl, perfluorohexyl, and perfluorooctyl;-fluoroalkyl-O-fluoroalkyl such as perfluoroethoxyethyl; —N(alkyl)₂;fluoro; or imidazolyl. In certain embodiments, LG is —O-phenyl.

With respect to compound of Formula (Bi), X is a halogen orpseudohalogen. Exemplary psuedohalogens include, but are not limited to,cyano (—CN) and thiocyanate (—SCN). In certain embodiments, X ishalogen. In certain particular embodiments, X is bromo.

With respect to a compound of Formula (B′i) (and, where applicable, theproduct of the reaction, a compound of Formula (Ci)), LG is a leavinggroup and M is a metal, such as Li, Na, K, and preferably Li.

In one aspect the present disclosure includes a method for manufacturinga C18 steroid compound of Formula (II) and, preferably, a compound ofFormula (IIA):

With respect to a compound of Formula (II) or Formula (IIA), each

independently represents a single bond or a double bond and each of thenumbered carbons is covalently attached to one or more hydrogen atomsand/or one or more R groups to complete the valency of the respectivecarbon atom.

In certain embodiments, the method comprises forming a B-ring from anintermediate ACD-ring containing compound of Formula (Eii):

whereinR^(CZ) is hydrogen or Si(R^(M))₃, wherein each R^(M) is independentlyselected from the group consisting of hydrogen, C₁₋₆-alkyl,trimethylsilyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, arylalkyl, and—OR^(MX), wherein R^(MX) is hydrogen, C₁₋₆-alkyl, or C₆₋₁₀-aryl; andeach of the numbered carbons is covalently attached to one or morehydrogen atoms and/or one or more R groups to complete the valency ofthe respective carbon atom. In certain embodiments, each R^(M) isC₁₋₆-alkyl. In some such embodiments, each R^(M) is methyl. In certainembodiments, at least one R^(M) is C₆₋₁₀-aryl and the remaining R^(M)are hydrogen or C₁₋₆-alkyl. In certain embodiments, at least one R^(M)is 5- to 10-membered heteroaryl (e.g., furyl) and the remaining R^(M)are hydrogen or C₁₋₆-alkyl.

In certain embodiments, the intermediate ACD-ring containing compound ofFormula (Eii) is formed by reacting a compound of Formula (Cii) with acompound of Formula (Dii):

whereinLG is a leaving group; and each R^(M) is independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, trimethylsilyl, C₆₋₁₀-aryl, 5-to 10-membered heteroaryl, arylalkyl, and —OR^(MX), wherein R^(MX) ishydrogen, C₁₋₆-alkyl, or C₆₋₁₀-aryl. Exemplary leaving groups include,but are not limited to, halogen, —O—Ar¹, where Ar¹ is a substituted orunsubstituted C₆₋₁₀-aryl or 5- to 10-membered heteroaryl, in particular—O-phenyl, and —OSO₂R^(1a), wherein R^(1a) is aryl, such as p-tolyl orphenyl; alkyl such as methyl or ethyl; fluoroalkyl such astrifluoromethyl, perfluorobutyl (C₄F₉), perfluoropentyl, perfluorohexyl,and perfluorooctyl; -fluoroalkyl-O-fluoroalkyl such asperfluoroethoxyethyl; —N(alkyl)₂; fluoro; or imidazolyl.

In certain embodiments, the method further comprises forming a compoundFormula (IIB′) from a compound of Formula (IIB) through Birch reductionand subsequent hydrolysis:

With respect to a compound of Formula (IIB), R^(AX) is C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,—C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, —S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to10-membered heteroaryl; and X is a halogen or pseudohalogen. Each

independently represents a single bond or a double bond.

In certain embodiments, the method further comprises forming a compoundof Formula (III) by (a) oxidation of a compound of Formula (IIA) to forma ketone of Formula (IIA′) and (b) enolization of the ketone of Formula(IIA′):

With respect to compounds of Formula (III), R^(DX) is C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,—C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to 10-memberedheteroaryl. Each

independently represents a single bond or a double bond.

In certain embodiments, the method further comprises forming a compoundof Formula (IV) by (a) C6-borylation/oxidation of a compound of Formula(IIC) to form a compound of Formula (IIC′) and (b) dearomative oxidationof the compound of Formula (IIC′):

With respect to compounds of Formula (IIC), X is a halogen orpseudohalogen. Each

independently represents a single bond or a double bond.

In certain embodiments, the method further comprises forming a compoundFormula (IIC″) through coupling a compound of Formula (IIB) with aboronic acid or related organometalloid coupling partner (i.e. boronicester, trialkylborane, etc):

With respect to a compound of Formula (IIB), X is a halogen orpseudohalogen; R⁶ is selected from the group consisting of hydrogen,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl,5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein R^(BX) isC₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl,or 5- to 10-membered heteroaryl. Each

independently represents a single bond or a double bond.

In certain embodiments, the method further comprises forming a compoundof Formula (IIA) by oxidizing a compound of Formula (IIA″):

With respect to a compound of Formula (IIA) and a compound of Formula(IIA″), each

independently represents a single bond or a double bond.

In one aspect, the present disclosure provides methods for producingenantiodefined polycyclic ring compounds. The methods of the presentdisclosure for producing enantiodefined polycyclic ring compounds andthe resulting compositions are exemplified in the following generalchemical scheme(s).

In certain embodiments, a steroidal tetracycle is produced from ahydrindane. Scheme 1 depicts an exemplary reaction for forming asteroidal tetracycle (G).

While the present disclosure is not limited to any particularmechanism(s) or mode(s) of action of the products of the synthesisprocess, it was contemplated that late-stage establishment of asteroidal tetracycle (i.e., steroidal A, B, C, D ring structure) asshown by an exemplary compound of Formula (Gi), below:

would be achieved through strategic formation of the C5-C6 bond byfunctionalization and activation of a tricyclic ACD-ring-containingsystem (as shown by an exemplary intermediate of Formula (Ei) below),

as described herein. (An exemplary Scheme 1 reaction is shown in Example2). Molecules of the general structure of intermediate of Formula (Ei)(e.g., functionalized/unsaturated hydrindanes), as shown above, arevaluable intermediates in the subsequent synthetic methods of thepresent disclosure.

In certain embodiments, such intermediate compounds of Formula (E) aboveare produced using one or more conventional reaction(s); in certainparticularly preferred examples of these embodiments. Scheme 2 depictsan exemplary reaction for forming a hydrindane of Formula (E).

While not limited to any particular mechanisms, the present disclosurecontemplates using metallacycle-mediated annulative cross-couplingreaction(s) between a suitably functionalized alkyne, exemplified byfunctionalized alkyne of Formula (D), reacted with a suitable chiralenyne, exemplified by chiral enyne of Formula (C) to produce theaforementioned functionalized hydrindane of Formula (E). (An exemplaryScheme 2 reaction is shown in Example 1).

In some exemplary embodiments of Scheme 1 and Scheme 2, R¹, R², R³, andR⁴ are each independently selected from the group consisting of C₁-C₄alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; —CF₃; halo; ═O; —OH;—O—(C₁-C₄-alkyl); —OCH₂F; —OCHF₃; —OCF₃; —OC(O)—(C₁-C₄-alkyl);—OC(O)—(C₁-C₄-alkyl); —OC(O)NH—(C₁-C₄-alkyl); —OC(O)N(C₁-C₄-alkyl)₂;—OC(S)NH—(C₁-C₄-alkyl); —OC(S)N(C₁-C₄-alkyl)₂; —SH; —S—(C₁-C₄-alkyl);—S(O)—(C₁-C₄-alkyl); —S(O)₂—(C₁-C₄-alkyl); —SC(O)—(C₁-C₄-alkyl);—SC(O)O—(C₁-C₄-alkyl); —NH₂; —N(H)—(C₁-C₄-alkyl); —N(C₁-C₄-alkyl)₂;—N(H)C(O)—(C₁-C₄-alkyl); —N(CH₃)C(O)—(C₁-C₄-alkyl); —N(H)C(O)—CF₃;—N(CH₃)C(O)—CF₃; —N(H)C(S)—(C₁-C₄-alkyl); —N(CH₃)C(S)—(C₁-C₄-alkyl);—N(H)S(O)₂—(C₁-C₄-alkyl); —N(H)C(O)NH₂; —N(H)C(O)NH—(C₁-C₄-alkyl);—N(CH₃)C(O)NH—(C₁-C₄-alkyl); —N(H)C(O)N(C₁-C₄-alkyl)₂;—N(CH₃)C(O)N(C₁-C₄-alkyl)₂; —N(H)S(O)₂NH₂; —N(H)S(O)₂NH—(C₁-C₄-alkyl);—N(CH₃)S(O)₂NH—(C₁-C₄-alkyl); —N(H)S(O)₂N(C₁-C₄-alkyl)₂;—N(CH₃)S(O)₂N(C₁-C₄-alkyl)₂; —N(H)C(O)O—(C₁-C₄-alkyl);—N(CH₃)C(O)O—(C₁-C₄-alkyl); —N(H)S(O)₂O—(C₁-C₄-alkyl);—N(CH₃)S(O)₂O—(C₁-C₄-alkyl); —N(CH₃)C(S)NH—(C₁-C₄-alkyl);—N(CH₃)C(S)N(C₁-C₄-alkyl)₂; —N(CH₃)C(S)O—(C₁-C₄-alkyl); —N(H)C(S)NH₂;—NO₂; —CO₂H; —CO₂—(C₁-C₄-alkyl); —C(O)N(H)OH; —C(O)N(CH₃)OH:—C(O)N(CH₃)OH; —C(O)N(CH₃)O—(C₁-C₄-alkyl); —C(O)N(H)—(C₁-C₄-alkyl);—C(O)N(C₁-C₄-alkyl)₂; —C(S)N(H)—(C₁-C₄-alkyl); —C(S)N(C₁-C₄-alkyl)₂;—C(NH)N(H)—(C₁-C₄-alkyl); —C(NH)N(C₁-C₄-alkyl)₂;—C(NCH₃)N(H)—(C₁-C₄-alkyl); —C(NCH₃)N(C₁-C₄-alkyl)₂;—C(O)—(C₁-C₄-alkyl); —C(NH)—(C₁-C₄-alkyl); —C(NCH₃)—(C₁-C₄-alkyl);—C(NOH)—(C₁-C₄-alkyl); —C(NOCH₃)—(C₁-C₄-alkyl); —CN; —CHO; —CH₂OH;—CH₂O—(C₁-C₄-alkyl); —CH₂NH₂; —CH₂N(H)—(C₁-C₄-alkyl);—CH₂N(C₁-C₄-alkyl)₂; C₆-C₁₄-aryl; 5- to 14-membered heteroaryl;C₃-C₁₄-cycloalkyl; and 5- to 14-membered heterocyclyl.

In certain embodiments, unless otherwise stated or indicated by context,a substitutent of a compound utilized in and/or produced by Scheme 1and/or Scheme 2, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, orheteroaryl, is optionally substituted with one or more of substituentswhich independently are: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —PO₃(R^(a))₂ whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

More particularly, one contemplated synthetic embodiment starting withsimple chiral precursors is described as follows.

Briefly, in one embodiment a suitable chiral (optically active)bifunctional reagent (e.g., a three carbon starting material such as,but not limited to, epichlorohydrin 5) that is transformed to asubstitute enyne (i.e., 6, prepared according to either: A) a two-stepprocedure, comprising (i) phenylpropargyl ether, n-BuLi, THF, −78° C. tort (17%); and (ii) 2-propenylmagnesium bromide, CuI, THF, −78° C. to rt(70%); or, B) a three-step procedure, comprising (i) phenylpropargylether, n-BuLi, THF, BF₃OEt₂, −78° C.; (ii) KOt-Bu, Et₂O; and (iii)2-propenylmagnesium bromide, CuI, THF, −78° C. to rt (63% over threesteps)). While this synthetic pathway was employed in preferredembodiments to generate enynes that were advanced to steroidal compoundsthrough the methods described in this invention, other pathways tofunctionalized enynes are understood to be compatible with the methodsof this invention (i.e., including but not limited to the use of asubstituted epoxyalcohol as described in Greszler, S. N., et al., J. Am.Chem. Soc. 2012, 134, 2766-2774, and Jeso, V., et al., J. Am. Chem.Soc., 2014, 136, 8209-8212). Intermolecular metallacycle-mediatedannulative cross-coupling of the enyne 6 with TMS-phenylacetylene 7delivers hydrindane 8.

More particularly, the present disclosure contemplates afunctionalization method wherein it is possible to install the steroidalC6 carbon in concert with revealing a reactive intermediate for B-ringformation. Preferably, a cyclopropanation reaction is used to accomplishthis, here selectively engaging the 1,1-disubstituted alkene of 8 toproduce the vinylcyclopropane intermediate 10. It is furthercontemplated, in certain specific embodiments, where the resultingcyclopropanation efficiency is undesirably low (or deemed inefficient)that overall yields can be increased (efficiency increased) byprotecting the secondary alcohol prior to cyclopropanation (i.e., as itscorresponding tertbutyldimethylsilyl ether (“TBS”)). In certainpreferred embodiments, the vinylcyclopropane intermediate 10 (or itsTBS-protected derivative) is then treated with TiCl₄ in nitromethane(optionally in the presence of a protic additive, e.g., isopropanol).

While the present disclosure is not limited to any particularmechanism(s), and the compositions and methods of the present disclosureare not intended to be so limited, the present disclosure contemplatesthat the reaction of TiCl₄ with the D-ring hydroxy group [(orpotentially with adventitious water, or an “O—H-containing” additive(i.e., isopropanol)] produces an in situ protic acid that convertsvinylcyclopropane intermediate 10 to a reactive homoallylic cationintermediate (depicted above in brackets) through a process ofprotodesilylation, protonation of the resulting styrenyl alkene, andsubsequent regioselective cyclopropane fragmentation. Ring closure isthen accomplished through a bond-forming process that likely procedes byusing the aromatic ring as a nucleophile in an intramolecularFriedel-Crafts alkylation, yielding an intermediate that is transformedto steroidal product 12 through loss of HBr (in 68% yield). In similar,but alternative embodiments, the reaction is augmented by the additionof suitable acid(s) in amounts and concentrations sufficient to yieldthe steroidal products of interest. It is understood that the “D-ring”C16-OH is not a required functionality for the acid-mediatedB-ring-forming process.

Another contemplated synthetic embodiment starting with simple chiralprecursors is described is depicted in the following reaction scheme:

This overall process is contemplated to provide an angularly substitutedtrans-fused hydrindane in a convergent manner from acyclic precursors aswell as to establish three σ_(C—C) bonds and two stereocenters (one ofwhich is quaternary).

In one aspect, the present disclosure includes intermediate compoundsuseful in the preparation of, inter alia, steroidal tetracyclesdisclosed herein.

In one particular aspect, the present disclosure provides anintermediate compound of Formula (Ei):

With respect to a compound of Formula (Ei), Cy is C₃₋₈-cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀-aryl, or 5- to 10-memberedheteroaryl;

each R^(M) is independently selected from the group consisting ofhydrogen, trimethylsilyl, C₁₋₆-alkyl, C₆₋₁₀-aryl, 5- to 10-memberedheteroaryl, arylalkyl, and —OR^(MX), wherein R^(MX) is hydrogen,C₁₋₆-alkyl, or C₆₋₁₀-aryl;

n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, 8, 9, and 10;

m is an integer selected from 0, 1, and 2;

R^(A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, hydroxy,—OR^(AX), —SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl, or two R^(A) together form an oxo,

-   -   wherein R^(AX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, —S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-membered        heteroaryl,    -   wherein R^(AY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to        10-membered heteroaryl,    -   wherein each of R^(Z1) and R^(Z2) are independently hydrogen,        C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,        C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, or        C₁₋₆-alkoxy;

R¹³ is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and

each R¹⁷ is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen, or two R^(17A) together form an oxo;

wherein any C₃₋₈-cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionally substitutedwith one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy.

In certain embodiments, Cy is a substituted or unsubstituted C₆₋₁₀-arylor 5- to 10-membered heteroaryl. In some such embodiments, Cy isunsubstituted phenyl. In some such embodiments, Cy is phenyl substitutedwith one or more C₁₋₆-alkyl, C₁₋₆-alkoxy, or halogen.

In certain embodiments, at least one R^(M) is C₁₋₆-alkyl and,preferably, all three R^(M) are C₁₋₆-alkyl (e.g., each R^(M) is methylto form trimethylsilyl).

In certain embodiments, R¹³ is C₁₋₆-alkyl.

In certain embodiments, each R¹⁷ is hydrogen.

In another particular aspect, the present disclosure provides anintermediate compound of Formula (Fi):

With respect to a compound of Formula (Fi), Cy is C₃₋₈-cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀-aryl, or 5- to 10-memberedheteroaryl;

each R^(M) is independently selected from the group consisting ofhydrogen, trimethylsilyl, C₁₋₆-alkyl, C₆₋₁₀-aryl, 5- to 10-memberedheteroaryl, arylalkyl, and —OR^(MX), wherein R^(MX) is hydrogen,C₁₋₆-alkyl, or C₆₋₁₀-aryl;

n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, 8, 9, and 10;

m is an integer selected from 0, 1, and 2;

R^(A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, hydroxy,—OR^(AX), —SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl, or two R^(A) together form an oxo,

-   -   wherein R^(AX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, —S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-membered        heteroaryl,    -   wherein R^(AY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to        10-membered heteroaryl,    -   wherein each of R^(Z1) and R^(Z2) are independently hydrogen,        C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,        C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, or        C₁₋₆-alkoxy;

R¹³ is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy;

each R¹⁷ is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen, or two R^(17A) together form an oxo; and

X¹ and X² are independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,halogen, oxygen, —OR^(BX), —SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1),—S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z))S(O)₂R^(Z2),C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl;

wherein any C₃₋₈-cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionally substitutedwith one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy.

In certain embodiments, Cy is a substituted or unsubstituted C₆₋₁₀-arylor 5- to 10-membered heteroaryl. In some such embodiments, Cy isunsubstituted phenyl. In some such embodiments, Cy is phenyl substitutedwith one or more C₁₋₆-alkyl, C₁₋₆-alkoxy, or halogen.

In certain embodiments, at least one R^(M) is C₁₋₆-alkyl and,preferably, all three R^(M) are C₁₋₆-alkyl (e.g., each R^(M) is methylto form trimethylsilyl).

In certain embodiments, R¹³ is C₁₋₆-alkyl.

In certain embodiments, each R¹⁷ is hydrogen.

In still other particular aspects, the present disclosure provides avinylcyclopropane intermediate of Formula (Fii):

With respect to a compound of Formula (Fii), X and Y represent a halogenatom (e.g., F, Cl, Br, and/or I) or in cases where a single halogen atomis present (i.e., X=Br), the other group (Y) can be a variety of othersubstituents including, but not limited to, alkyl, aryl, heteroaryl, andother heteroatomic groups capable of supporting the subsequent ringclosing reaction (i.e., OR, NR, NR₂SR, where R=alkyl, aryl, heteroaryl,acyl, and the like). Moreover, R¹, R², and R³ can be as described above,for example, each of R¹, R², and R³ may be independently selected fromthe group consisting of C₁-C₄ alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; —CF₃;halo; ═O; —OH; —O—(C₁-C₄-alkyl); —OCH₂F; —OCHF₃; —OCF₃;—OC(O)—(C₁-C₄-alkyl); —OC(O)—(C₁-C₄-alkyl); —OC(O)NH—(C₁-C₄-alkyl);—OC(O)N(C₁-C₄-alkyl)₂; —OC(S)NH—(C₁-C₄-alkyl); —OC(S)N(C₁-C₄-alkyl)₂;—SH; —S—(C₁-C₄-alkyl); —S(O)—(C₁-C₄-alkyl); —S(O)₂—(C₁-C₄-alkyl);—SC(O)—(C₁-C₄-alkyl); —SC(O)O—(C₁-C₄-alkyl); —NH₂; —N(H)—(C₁-C₄-alkyl);—N(C₁-C₄-alkyl)₂; —N(H)C(O)—(C₁-C₄-alkyl); —N(CH₃)C(O)—(C₁-C₄-alkyl);—N(H)C(O)—CF₃; —N(CH₃)C(O)—CF₃; —N(H)C(S)—(C₁-C₄-alkyl);—N(CH₃)C(S)—(C₁-C₄-alkyl); —N(H)S(O)₂—(C₁-C₄-alkyl); —N(H)C(O)NH₂;—N(H)C(O)NH—(C₁-C₄-alkyl); —N(CH₃)C(O)NH—(C₁-C₄-alkyl);—N(H)C(O)N(C₁-C₄-alkyl)₂; —N(CH₃)C(O)N(C₁-C₄-alkyl)₂; —N(H)S(O)₂NH₂;—N(H)S(O)₂NH—(C₁-C₄-alkyl); —N(CH₃)S(O)₂NH—(C₁-C₄-alkyl);—N(H)S(O)₂N(C₁-C₄-alkyl)₂; —N(CH₃)S(O)₂N(C₁-C₄-alkyl)₂;—N(H)C(O)O—(C₁-C₄-alkyl); —N(CH₃)C(O)O—(C₁-C₄-alkyl);—N(H)S(O)₂O—(C₁-C₄-alkyl); —N(CH₃)S(O)₂O—(C₁-C₄-alkyl);—N(CH₃)C(S)NH—(C₁-C₄-alkyl); —N(CH₃)C(S)N(C₁-C₄-alkyl)₂;—N(CH₃)C(S)O—(C₁-C₄-alkyl); —N(H)C(S)NH₂; —NO₂; —CO₂H;—CO₂—(C₁-C₄-alkyl); —C(O)N(H)OH; —C(O)N(CH₃)OH: —C(O)N(CH₃)OH;—C(O)N(CH₃)O—(C₁-C₄-alkyl); —C(O)N(H)—(C₁-C₄-alkyl);—C(O)N(C₁-C₄-alkyl)₂; —C(S)N(H)—(C₁-C₄-alkyl); —C(S)N(C₁-C₄-alkyl)₂;—C(NH)N(H)—(C₁-C₄-alkyl); —C(NH)N(C₁-C₄-alkyl)₂;—C(NCH₃)N(H)—(C₁-C₄-alkyl); —C(NCH₃)N(C₁-C₄-alkyl)₂;—C(O)—(C₁-C₄-alkyl); —C(NH)—(C₁-C₄-alkyl); —C(NCH₃)—(C₁-C₄-alkyl);—C(NOH)—(C₁-C₄-alkyl); —C(NOCH₃)—(C₁-C₄-alkyl); —CN; —CHO; —CH₂OH;—CH₂O—(C₁-C₄-alkyl); —CH₂NH₂; —CH₂N(H)—(C₁-C₄-alkyl);—CH₂N(C₁-C₄-alkyl)₂; C₆-C₁₄-aryl; 5- to 14-membered heteroaryl;C₃-C₁₄-cycloalkyl; and 5- to 14-membered heterocyclyl.

In certain embodiments, an alkyne of Formula (D) is used to form anA-CD-containing tricycle of Formula (E), which is then used to produce asteroidal tetracycle. As illustrated in FIG. 1, the methods of thepresent disclosure and the chemical pathways therein are useful forgenerating a wide range of steroidal systems in a concise andenantiospecific fashion.

Certain particular exemplary embodiments are described in the Examplesand in the following Tables 1-8. Common Notations in Tables 1-8: (a)yield reported is for the combination of diene isomers (trans-fusedproduct containing an exo-1,1-disubstituted alkene+bicyclic productcontaining an endocyclic diene); (b) stereoselectivity for theannulation process (trans:cis) is typically ˜6:1; (c) yield reported isfor the 2-3 step sequence; and (d) regioselectivity is based on ¹H NMRof the crude reaction product).

TABLE 1 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

69

26^(e)

Notation: ^(e)cyclization sequence was conducted without protection ofthe C16 hydroxy group.

Table 1, demonstrates the facility of certain embodiments of the presentdisclosure wherein an ent-steroid, ent-6 (derived from(+)-epichlorohydrin 5), was converted to steroidal product ent-12. Theefficiency of the two-step ring-closing process (ent-8→ent-12)illustrates the challenge of accomplishing cyclopropanation in thepresence of the C16-OH.

TABLE 2 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

43

57

TABLE 3 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

57

33

Table 2 illustrates that in certain embodiments the efficiency of theoverall process is substantially greater if the C16 hydroxy group issilylated prior to cyclopropanation and, when taken with theillustration in Table 3, demonstrates the capability of the presentmethods to produce A-ring aromatic steroids containing variedoxygenation patterns (compounds 15 and 18).

TABLE 4 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

51

—^(f)

Notation: ^(f)yield for this unselective process was not determined.

As illustrated in Table 4, the use of the p-chloro-substitutedphenylacetylene 19 led to the discovery that the final ring closure canproceed with additional rearrangement. In this embodiment, steroidalproducts 21a and 21b were produced in roughly equal proportions. Whilethe present disclosure is not limited to any particular mechanism(s), itis contemplated that this observation is consistent with the proposed(non-limiting) mechanism depicted in FIG. 2, where cyclization isthought to proceed either through direct Friedel-Crafts alkylation(II→III→F), or by initial formation of a spirocyclic intermediate andsubsequent rearrangement with selective migration of C9 (II→IV→G).

TABLE 5 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

55

34

Table 5 illustrates that certain preferred embodiments of the presentdisclosure achieve high levels of selectivity in favor of ring closureby rearrangement. In particular, in this embodiment, thep-methoxy-substituent of compound 23 plays a significant role in biasingthe course of reaction. While the present disclosure is not limited toany particular mechanism(s), it is contemplated that this observation islikely due to the electronic contribution of the electron rich aromatic,favoring the formation of a spirocyclic intermediate similar tointermediate IV represented in FIG. 2. The production of theC2-methoxy-substituted steroid 24 was found to proceed with very highlevels of selectivity (rs≥20:1).

TABLE 6 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

49

31

Table 6, illustrates still further embodiments of the present disclosurewherein the modification of A-ring substitution (compound 26) restored apreference for cyclization without rearrangement. More particularly, inthis embodiment, cyclization delivered the C3-methoxy-substitutedsteroid 27 as a single regioisomer in a 31% yield (over three steps).While not limited to any particular mechanism(s), it is contemplatedthat this observation is consistent with steric effects stemming fromthe chloride substituents that may dissuade oxonium ion formation in thespirocyclic intermediate (i.e., an oxonium ion intermediate would bedestabilized by significant 1,5-interactions between the methyl group ofthe oxonium ion and one of the ortho chlorine substituents).

TABLE 7 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

52

68

TABLE 8 A-CD Tricycle Alkyne of Yield (trans isomer:endo Yield^(c)19-nor Steroid Formula (D) (%) diene)^(a,b) (%) (rs)^(d)

49

46

Table 7 and Table 8 provide yet additional embodiments and examples thatillustrate the utility and selectivity of the various methods of thepresent disclosure to produce steroidal products having varying A-ringstructures and substitutions.

C. EXEMPLARY STEROIDAL COMPOUNDS

In one aspect, this disclosure provides a compound, intermediate, orsalt thereof, wherein the compound either has a structure correspondingto Formula (IA), Formula (IB), Formula (IC), or Formula (ID), or couldbe transformed to such structures by methods well known to those skilledin the art of synthetic organic chemistry:

wherein

each R^(2A) and each R^(4A) is independently absent or, when present,selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, hydroxy,—OR^(AX), —SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl, or two R^(2A) together or two R^(4A)together form an oxo,

-   -   wherein R^(AX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, —C(O)—O—C₁₋₁₀-alkyl, —C(O)—O—C₆₋₁₀-aryl,        —C(O)—O-heteroaryl, —C(O)—NR^(Z1)R^(Z2), —S(O)₂R^(Z1),        C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl,    -   wherein R^(AY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to        10-membered heteroaryl,    -   wherein each of R^(Z1) and R^(Z2) are independently hydrogen,        C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,        C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, or        C₁₋₆-alkoxy;

each R^(3A) is independently absent or, when present, selected from thegroup consisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, —OR^(AX), —SR^(AY), —S(O)₂NR^(Z1)R^(Z2),—S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2),—N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to 10-membered heteroaryl;

R^(6A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, oxygen, boronicacid, boronic acid ester, —OR^(BX), —SR^(BY), —S(O)₂NR^(Z1)R^(Z2),—S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2),—N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₆₋₁₀-aryl-C₁₋₆-alkyl, C₆₋₁₀-aryl-C₂₋₆-alkenyl, andC₆₋₁₀-aryl-C₂₋₆-alkynyl,

-   -   wherein R^(BX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl,    -   wherein R^(BY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to        10-membered heteroaryl;

R^(11A) is selected from the group consisting of hydrogen, oxygen, andOR^(CX),

-   -   wherein R^(CX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl;

R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy;

each R^(16A) is independently selected from the group consisting ofhydrogen, hydroxy, —OR^(DX), —SR^(DY), —S(O)₂NR^(Z1)R^(Z2),—S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2),—N(R^(Z1))S(O)₂R^(Z2), and —C(O)—C₁₋₁₀-alkyl, or two R^(16A) togetherform an oxo,

-   -   wherein R^(DX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,        C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,        —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl,    -   wherein R^(DY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to        10-membered heteroaryl;

each R^(17A) is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen, or two R^(17A) together form an oxo;

each ---- independently represents a single bond or a double bond;

the A ring is saturated, partially unsaturated, or completelyunsaturated; and

the B ring is saturated, partially unsaturated, or completelyunsaturated;

wherein any C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, orC₁₋₆-alkoxy.

In one aspect, this disclosure provides a compound or salt thereof,wherein the compound has a structure corresponding to Formula (IA-1) orFormula (IA-2), or could be transformed to such structures by methodswell known to those skilled in the art of synthetic organic chemistry:

wherein

each of R^(2A) and R^(4A) are independently selected from the groupconsisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, hydroxy, —OR^(AX), —SR^(AY),—S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2),—N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to10-membered heteroaryl;

R^(3A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(AX),—SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl;

R^(6A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(BX),—SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl;

R^(11A) is selected from the group consisting of hydrogen, oxygen, andOR^(CX),

-   -   wherein if R^(11A) is oxygen, then        represents a double bond and if R^(11A) is hydrogen or OR^(CX),        then        represents a single bond;

R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and

each R^(17A) is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen;

wherein any C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, orC₁₋₆-alkoxy.

In certain embodiments, R^(2A) and R^(4A) each is independently selectedfrom the group consisting of hydrogen, C₁₋₆-alkyl, halogen, hydroxy, and—OR^(AX); R^(3A) is selected from the group consisting of hydrogen,C₁₋₆-alkyl, and —OR^(AX); R^(6A) is selected from the group consistingof hydrogen, halogen, —OR^(BX), C₆₋₁₀-aryl optionally substituted withone or more C₁₋₆-alkoxy, and C₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein theC₆₋₁₀-aryl of the C₆₋₁₀-aryl-C₂₋₆-alkynyl is unsubstituted; R^(11A) ishydrogen; R^(13A) is selected from the group consisting of C₁₋₆-alkyland C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is unsubstituted; and each R^(17A) is hydrogen.

In one aspect, this disclosure provides a compound or salt thereof,wherein the compound has a structure corresponding to Formula (IB-1) orFormula (IB-2), or could be transformed to such structures by methodswell known to those skilled in the art of synthetic organic chemistry:

wherein

each of R^(2A) and R^(4A) are independently selected from the groupconsisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, hydroxy, —OR^(AX), —SR^(AY),—S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2),—N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to10-membered heteroaryl;

R^(3A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(AX),—SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl;

R^(6A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(BX),—SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl;

R^(11A) is selected from the group consisting of hydrogen, and OR^(CX),

-   -   wherein if R^(11A) is oxygen, then        represents a double bond and if R^(11A) is hydrogen or OR^(CX),        then        represents a single bond;

R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and

each R^(17A) is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen;

wherein any C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, orC₁₋₆-alkoxy.

In certain embodiments, R^(2A) and R^(4A) each is independently selectedfrom the group consisting of hydrogen, C₁₋₆-alkyl, halogen, hydroxy, and—OR^(AX); R^(3A) is selected from the group consisting of hydrogen,C₁₋₆-alkyl, and —OR^(A); R^(6A) is selected from the group consisting ofhydrogen, halogen, —OR^(BX), C₆₋₁₀-aryl optionally substituted with oneor more C₁₋₆-alkoxy, and C₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein the C₆₋₁₀-arylof the C₆₋₁₀-aryl-C₂₋₆-alkynyl is unsubstituted; R^(11A) is hydrogen;R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is unsubstituted; and each R^(17A) is hydrogen.

In one aspect, this disclosure provides a compound or salt thereof,wherein the compound has a structure corresponding to Formula (IC-1) orFormula (IC-2), or could be transformed to such structures by methodswell known to those skilled in the art of synthetic organic chemistry:

wherein

each of R^(2A) and R^(4A) are independently selected from the groupconsisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, hydroxy, —OR^(AX), —SR^(AY),—S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2),—N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to10-membered heteroaryl;

R^(3A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(AX),—SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl;

R^(6A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(BX),—SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl;

R^(11A) is selected from the group consisting of hydrogen, oxygen, andOR^(CX),

-   -   wherein if R^(11A) is oxygen, then        represents a double bond and if R^(11A) is hydrogen or OR^(CX),        then        represents a single bond;

R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and

each R^(17A) is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen;

wherein any C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, orC₁₋₆-alkoxy.

In certain embodiments, R^(2A) and R^(4A) each is independently selectedfrom the group consisting of hydrogen, C₁₋₆-alkyl, halogen, hydroxy, and—OR^(AX); R^(3A) is selected from the group consisting of hydrogen,C₁₋₆-alkyl, and —OR^(AX); R^(6A) is selected from the group consistingof hydrogen, halogen, —OR^(BX), C₆₋₁₀-aryl optionally substituted withone or more C₁₋₆-alkoxy, and C₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein theC₆₋₁₀-aryl of the C₆₋₁₀-aryl-C₂₋₆-alkynyl is unsubstituted; R^(11A) ishydrogen; R^(13A) is selected from the group consisting of C₁₋₆-alkyland C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is unsubstituted; and each R^(17A) is hydrogen.

In one aspect, this disclosure provides a compound or salt thereof,wherein the compound has a structure corresponding to Formula (ID-1) orFormula (ID-2), or could be transformed to such structures by methodswell known to those skilled in the art of synthetic organic chemistry:

wherein

each of R^(2A) and R^(4A) are independently selected from the groupconsisting of hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, halogen, hydroxy, —OR^(AX), —SR^(AY),—S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1), —NR^(Z1)R^(Z2),—N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, and 5- to10-membered heteroaryl;

R^(3A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(AX),—SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl;

R^(6A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, —OR^(BX),—SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,5- to 10-membered heteroaryl, C₆₋₁₀-aryl-C₁₋₆-alkyl,C₆₋₁₀-aryl-C₂₋₆-alkenyl, and C₆₋₁₀-aryl-C₂₋₆-alkynyl;

R^(11A) is selected from the group consisting of hydrogen, oxygen, andOR^(CX),

-   -   wherein if R^(11A) is oxygen, then        represents a double bond and if R^(11A) is hydrogen or OR^(CX),        then        represents a single bond;

R^(13A) is selected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl is optionally substitutedone or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and

each R^(17A) is independently selected from the group consisting ofhydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,and halogen;

wherein any C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, orC₁₋₆-alkoxy.

In certain embodiments, R^(2A) and R^(4A) each is independently selectedfrom the group consisting of hydrogen, C₁₋₆-alkyl, halogen, hydroxy, and—OR^(AX); R^(3A) is selected from the group consisting of hydrogen,C₁₋₆-alkyl, and —OR^(AX); R^(6A) is selected from the group consistingof hydrogen, halogen, —OR^(BX), C₆₋₁₀-aryl optionally substituted withone or more C₁₋₆-alkoxy, and C₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein theC₆₋₁₀-aryl of the C₆₋₁₀-aryl-C₂₋₆-alkynyl is unsubstituted; R^(11A) ishydrogen; R^(13A) is selected from the group consisting of C₁₋₆-alkyland C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is unsubstituted; and each R^(17A) is hydrogen.

R^(2A)

In certain embodiments of any aspect disclosed herein, R^(2A) isselected from the group consisting of hydrogen, C₁₋₆-alkyl, halogen,hydroxy, and —OR^(AX), wherein R^(AX) is R^(AX) is C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,—C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, —C(O)—O—C₁₋₁₀-alkyl,—C(O)—O—C₆₋₁₀-aryl, —C(O)—O-heteroaryl, —C(O)—NR^(Z1)R^(Z2),—S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl and whereineach of R^(Z1) and R^(Z2) are independently hydrogen, C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, or C₁₋₆-alkoxy.

In some such embodiments, R^(2A) is hydrogen. In some such embodiments,R^(2A) is C₁₋₆-alkyl, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some suchembodiments, R^(2A) is halogen, including, but not limited to, fluoro orchloro. In some such embodiments, R^(2A) is hydroxy. In some suchembodiments, R^(2A) is —OR^(AX).

R^(3A)

In certain embodiments of any aspect disclosed herein, R^(3A) isselected from the group consisting of hydrogen, C₁₋₆-alkyl, and —OR^(A).

In some such embodiments, R^(3A) is hydrogen. In some such embodiments,R^(3A) is C₁₋₆-alkyl, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some suchembodiments, R^(3A) is —OR^(AX).

R^(4A)

In certain embodiments of any aspect disclosed herein, R^(4A) isselected from the group consisting of hydrogen, C₁₋₆-alkyl, halogen,hydroxy, and —OR^(AX), wherein R^(AX) is R^(AX) is C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl,—C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, —C(O)—O—C₁₋₁₀-alkyl,—C(O)—O—C₆₋₁₀-aryl, —C(O)—O-heteroaryl, —C(O)—NR^(Z1)R^(Z2),—S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl and whereineach of R^(Z1) and R^(Z2) are independently hydrogen, C₁₋₆-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, or C₁₋₆-alkoxy.

In some such embodiments, R^(4A) is hydrogen. In some such embodiments,R^(4A) is C₁₋₆-alkyl, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some suchembodiments, R^(4A) is halogen, including, but not limited to, fluoro orchloro. In some such embodiments, R^(4A) is hydroxy. In some suchembodiments, R^(4A) is —OR^(AX).

R^(AX)

In certain embodiments of any aspect disclosed herein, R^(AX) isC₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,—C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl,—C(O)—O—C₁₋₁₀-alkyl, —C(O)—O—C₆₋₁₀-aryl, —C(O)—O-heteroaryl,—C(O)—NR^(Z1)R^(Z2), —S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-memberedheteroaryl.

In some such embodiments, R^(AX) is C₁₋₆-alkyl. In some suchembodiments, R^(AX) is C₂₋₁₀-alkenyl. In some such embodiments, R^(AX)is C₂₋₁₀-alkynyl. In some such embodiments, R^(AX) is C₁₋₁₀-haloalkyl.In some such embodiments, R^(AX) is —C(O)—C₁₋₁₀-alkyl. In some suchembodiments, R^(AX) is —C(O)—C₆₋₁₀-aryl. In some such embodiments,R^(AX) is —C(O)-heteroaryl. In some such embodiments, R^(AX) is—C(O)—O—C₁₋₁₀-alkyl. In some such embodiments, R^(AX) is—C(O)—O—C₆₋₁₀-aryl. In some such embodiments, R^(AX) is—C(O)—O-heteroaryl. In some such embodiments, R^(AX) is C₆₋₁₀-aryl. Insome such embodiments, R^(AX) is 5- to 10-membered heteroaryl. In somesuch embodiments, R^(AX) is —C(O)—NR^(Z1)R^(Z2). In some suchembodiments, R^(AX) is —S(O)₂R^(Z1).

R^(Z1)

In certain embodiments of any aspect disclosed herein, R^(Z1) ishydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, or C₁₋₆-alkoxy.

In some such embodiments, R^(Z1) is hydrogen. In some such embodiments,R^(Z1) is C₁₋₆-alkyl. In some such embodiments, R^(Z1) is C₂₋₁₀-alkenyl.In some such embodiments, R^(Z1) is C₂₋₁₀-alkynyl. In some suchembodiments, R^(Z1) is C₁₋₁₀-haloalkyl. In some such embodiments, R^(Z1)is C₆₋₁₀-aryl. In some such embodiments, R^(Z1) is 5- to 10-memberedheteroaryl. In some such embodiments, R^(Z1) is hydroxy. In some suchembodiments, R^(Z1) is C₁₋₆-alkoxy.

R^(Z2)

In certain embodiments of any aspect disclosed herein, R^(Z2) ishydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, or C₁₋₆-alkoxy.

In some such embodiments, R^(Z2) is hydrogen. In some such embodiments,R^(Z2) is C₁₋₆-alkyl. In some such embodiments, R^(Z2) is C₂₋₁₀-alkenyl.In some such embodiments, R^(Z2) is C₂₋₁₀-alkynyl. In some suchembodiments, R^(Z2) is C₁₋₁₀-haloalkyl. In some such embodiments, R^(Z2)is C₆₋₁₀-aryl. In some such embodiments, R^(Z2) is 5- to 10-memberedheteroaryl. In some such embodiments, R^(Z2) is hydroxy. In some suchembodiments, R^(Z2) is C₁₋₆-alkoxy.

R^(6A)

In certain embodiments of any aspect disclosed herein, R^(6A) isselected from the group consisting of hydrogen, halogen, —OR^(BX),C₆₋₁₀-aryl optionally substituted with one or more C₁₋₆-alkoxy, andC₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₂₋₆-alkynyl is substituted or unsubstituted.

In some such embodiments, R^(6A) is hydrogen. In some such embodiments,R^(6A) is halogen. In some such embodiments, R^(6A) is —OR^(BX). In somesuch embodiments, R^(6A) is unsubstituted C₆₋₁₀-aryl. In some suchembodiments, R^(6A) is C₆₋₁₀-aryl substituted with one or moreC₁₋₆-alkoxy. In some such embodiments, R^(6A) isC₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₂₋₆-alkynyl is unsubstituted.

R^(BX)

In certain embodiments of any aspect disclosed herein, R^(BX) isC₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,—C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5-to 10-membered heteroaryl.

In some such embodiments, R^(BX) is C₁₋₆-alkyl. In some suchembodiments, R^(BX) is C₂₋₁₀-alkenyl. In some such embodiments, R^(BX)is C₂₋₁₀-alkynyl. In some such embodiments, R^(BX) is C₁₋₁₀-haloalkyl.In some such embodiments, R^(BX) is —C(O)—C₁₋₁₀-alkyl. In some suchembodiments, R^(BX) is —C(O)—C₆₋₁₀-aryl. In some such embodiments,R^(BX) is —C(O)-heteroaryl. In some such embodiments, R^(BX) isC₆₋₁₀-aryl. In some such embodiments, R^(BX) is 5- to 10-memberedheteroaryl.

R^(11A)

In certain embodiments of any aspect disclosed herein, R^(11A) isselected from the group consisting of hydrogen, oxygen (double bonded tothe C11 carbon atom), and OR^(CX)

In some such embodiments, R^(11A) is hydrogen. In some such embodiments,R^(11A) is oxygen (double bonded to the C11 carbon atom). In some suchembodiments, R^(11A) is OR^(CX).

R^(CX)

In certain embodiments of any aspect disclosed herein, R^(CX) isC₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,—C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl, C₆₋₁₀-aryl, or 5-to 10-membered heteroaryl.

In some such embodiments, R^(CX) is C₁₋₆-alkyl. In some suchembodiments, R^(CX) is C₂₋₁₀-alkenyl. In some such embodiments, R^(CX)is C₂₋₁₀-alkynyl. In some such embodiments, R^(CX) is C₁₋₁₀-haloalkyl.In some such embodiments, R^(CX) is —C(O)—C₁₋₁₀-alkyl. In some suchembodiments, R^(CX) is —C(O)—C₆₋₁₀-aryl. In some such embodiments,R^(CX) is —C(O)-heteroaryl. In some such embodiments, R^(CX) isC₆₋₁₀-aryl. In some such embodiments, R^(CX) is 5- to 10-memberedheteroaryl.

R^(13A)

In certain embodiments of any aspect disclosed herein, R^(13A) isselected from the group consisting of C₁₋₆-alkyl andC₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is substituted or unsubstituted.

In some such embodiments, R^(13A) is C₁₋₆-alkyl. In some suchembodiments, R^(13A) is C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl ofthe C₆₋₁₀-aryl-C₁₋₆-alkyl is unsubstituted. In some such embodiments,R^(13A) is C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein the C₆₋₁₀-aryl of theC₆₋₁₀-aryl-C₁₋₆-alkyl is substituted.

R^(17A)

In certain embodiments of any aspect disclosed herein, R^(17A) isselected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, and halogen.

In some such embodiments, R^(17A) is hydrogen. In some such embodiments,R^(17A) is C₁₋₁₀-alkyl. In some such embodiments, R^(17A) isC₂₋₁₀-alkenyl. In some such embodiments, R^(17A) is C₂₋₁₀-alkynyl. Insome such embodiments, R^(17A) is C₁₋₁₀-haloalkyl. In some suchembodiments, R^(17A) is halogen.

In one aspect, this disclosure provides a compound or salt thereof,wherein the compound has a structure corresponding to one of thefollowing compounds:

The present disclosure provides enantiospecific methods of producingsteroids from readily available chiral starting materials that can bedesigned to comprise a range of steroidal systems (and semi- orpartial-steroidal systems) preferentially further encompassingadditional substitution(s) and varying stereochemistry. Notably, FIG. 3Aand Example 2W (steroid 34), Example 2Y (steroid 35), Example 2Z(steroid 36), Example 3A (steroid 37), Example 4B (steroid 38), Example5A (steroid 39), Example 6A (steroid 40), Example 7A (steroid 41), andFIG. 3C (steroids 27 and 43) among other embodiments, provide exemplarymethods and resulting steroidal compositions encompassing variedadditional substitution(s) and stereochemistries. Similarly, FIG. 3B andExample 8A (steroid ent-12) describe one embodiment of a method whereinmultigram quantities of an enantiodefined steroidal product can bereadily obtained.

In steroidal products 34 and 35, the C13 quaternary center at thejunction of rings C and D was altered simply by changing the Grignardreagent used to prepare the initial enyne for annulation (R¹=Et or Bn).In product 36, the stereochemistry at C14 was altered by using a variantof the metallacycle-mediated annulation process that furnishes thecis-fused isomer. (Kim, W. S., et al., Tetrahedron Lett., 56, 3557-3559[2015]). Success here demonstrated that the relative stereochemistry ofthe CD-ring fusion (cis- or trans-fused) did not significantly impactthe overall success of the steroid synthesis. Finally, simple functionalgroup manipulations can be used to gain access to steroidal compositionspossessing varied structure within each of the four rings of thetetracycle (steroid products 37-41). In one such embodiment, the presentmethods provide a means of producing a stable naphthoquinone methide(steroid 39). Finally, as depicted in FIG. 3B, the present synthesismethods and pathway are capable of producing multigram quantities ofsteroidal products. In one such exemplary embodiment, 4.0 g of steroident-12 was prepared in just five steps from epoxide 42 with an overallisolated yield of 20%.

In still further embodiments, the present disclosure provides syntheticmethods and pathways to produce ent-steroidal antipodes of medicinallyrelevant agents. For example, 16-hydroxyestratrienes have beenidentified as synthetic estrogens that have a dissociation in favor oftheir estrogenic action on bone rather than the uterus. (FIG. 3C). Inone such example, while estra-1,3,5(10),6,8-pentaene-3,16α-diol is arepresentative member of this class, its enantiomer has never beendescribed. Because the enantiomer of estradiol is known to haveneurological activity of potential value for the treatment of traumaticbrain injury, and lacks activity as an estrogenic compound, ent-estranesprovide a broader class of steroidal compounds with useful“non-steroidal” pharmaceutical properties. More particularly, one of theproducts from this synthesis pathway (steroid 27) can be easilytransformed to ent-estra-1,3,5(10),6,8-pentaene-3,16α-diol (steroid 43).(FIG. 3C).

In yet another embodiment, steroidal compound 39, a novel syntheticent-steroid prepared using methods of the present disclosure,demonstrated marked growth inhibition in three human cancer cell lineswith 50% inhibitory concentrations of 1.2-4 μM (0.32-1.07 μg/mL) ((FIG.3D); cells were plated at 1000 cells/well of a 96 well plate. Thefollowing day, compound 39 was added in 2-fold dilutions (8wells/concentration). After 7 days growth, cells were lysed and analyzedfor total DNA content as previously described in Montano, R., et al.,Mol Cancer Therap., 2012, 11, [427-438]).

D. METHODS OF USE

In at least one aspect, the present disclosure includes a method fortreating or preventing a proliferative disease in a subject in need ofsuch treatment or prevention. In certain embodiments, the subject is amammal. In certain embodiments, the mammal is a human. The proliferativedisease may be, for example, associated with: 1) the pathologicalproliferation of normally quiescent cells; 2) the pathological migrationof cells from their normal location (e.g., metastasis of neoplasticcells); or 3) pathological angiogenesis as in proliferative retinopathyand tumor metastasis. Exemplary proliferative diseases include cancers(i.e., “malignant neoplasms”), benign neoplasms, angiogenesis,inflammatory diseases, and autoimmune diseases. In particular, exemplarycancers that may treated or prevented include breast cancer, prostatecancer, ovarian cancer, acute myeloid leukemia, and glioma.

Another aspect of the present disclosure includes a method for treatingor preventing schizophrenia in a subject in need of such treatment orprevention. In certain embodiments, the subject is a mammal. In certainembodiments, the mammal is a human.

Still another aspect of the present disclosure includes a method fortreating or preventing neurodegeneration in a subject in need of suchtreatment or prevention. In certain embodiments, the subject is amammal. In certain embodiments, the mammal is a human. In some suchembodiments, the human subject is suffering from or at risk for aneurodegenerative disease such as spinal cord injury (SCI), multiplesclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD).

Yet another aspect of the present disclosure includes a method fortreating or preventing neuropathic pain in a subject in need of suchtreatment or prevention. In certain embodiments, the subject is amammal. In certain embodiments, the mammal is a human.

One aspect of the present disclosure includes a method for treating orpreventing a disease mediated by ER-β in a subject in need of suchtreatment or prevention. In certain embodiments, the subject is amammal. In certain embodiments, the mammal is a human.

Another aspect of the present disclosure includes a method for treatingor preventing a disease treatable or preventable by selectivelymodulating ER-β in a subject in need of such treatment or prevention. Incertain embodiments, the subject is a mammal. In certain embodiments,the mammal is a human.

In certain embodiments, for any of the aforementioned aspects, themethods comprise administering to the subject a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. In some such embodiments, the methods compriseadministering to the subject a therapeutically effective amount of acompound of Formula (IA) or a pharmaceutically acceptable salt thereof.In some such embodiments, the methods comprise administering to thesubject a therapeutically effective amount of a compound of Formula (IB)or a pharmaceutically acceptable salt thereof. In some such embodiments,the methods comprise administering to the subject a therapeuticallyeffective amount of a compound of Formula (IC) or a pharmaceuticallyacceptable salt thereof. In some such embodiments, the methods compriseadministering to the subject a therapeutically effective amount of acompound of Formula (ID) or a pharmaceutically acceptable salt thereof.In some such embodiments, the methods comprise administering to thesubject a therapeutically effective amount of Compound 39 or apharmaceutically acceptable salt thereof. In some such embodiments, themethods comprise administering to the subject a therapeuticallyeffective amount of Compound 205b or a pharmaceutically acceptable saltthereof.

In certain embodiments, for any of the aforementioned aspects, themethods comprise administering to the subject a therapeuticallyeffective amount of a compound of Formula (II) or a pharmaceuticallyacceptable salt thereof.

The preferred total daily dose of the compound or salt (administered insingle or divided doses) is typically from about 0.001 to about 100mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even morepreferably from about 0.01 to about 10 mg/kg (i.e., mg of the compoundor salt per kg body weight). In certain embodiments, dosage unitcompositions contain such amounts or submultiples thereof to make up thedaily dose. In many instances, the administration of the compound orsalt will be repeated a plurality of times. In certain embodiments,multiple doses per day typically may be used to increase the total dailydose, if desired.

Factors affecting the preferred dosage regimen include the type, age,weight, sex, diet, and condition of the patient; the severity of thepathological condition; the route of administration; pharmacologicalconsiderations, such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular compound or salt used; whether adrug delivery system is utilized; and whether the compound or salt isadministered as part of a drug combination. Thus, the dosage regimenactually employed can vary widely, and therefore, can derive from thepreferred dosage regimen set forth above.

The activity of a compound can be determined using various knownmethods. For example, the anti-proliferative activity of a compound canbe determined using various known methods, including in vitro and invivo antiproliferative assays using cancer cell lines such as MDA-MB-231(human breast adenocarcinoma), AsPC-1 (human pancreas adenocarcinomaascites metastasis), and A549 (lung carcinoma).

In at least one aspect, the present disclosure provides methods forproducing one or more steroids of the natural enantiomericconfiguration. Natural steroids, in these specific embodiments, aretaken as being medically, pharmaceutically, or biologically relevantsteroids otherwise produced by steroidogenesis in nature (i.e., in ananimal, fungus, or plant). In preferred embodiments, the presentdisclosure provides methods for concise and enantiospecific synthesis ofnat- and/or ent-steroid species comprising (or chemically related to) alicensed steroid drug product and/or active ingredient (e.g., licensedby recognized regulatory agency or body such as, but not limited to,the: Food and Drug Administration (“FDA”), European Medicines Agency(“EMA”), The Therapeutic Goods Administration (“TGA”), China Food andDrug Administration (“CFDA”), The Central Drugs Standard ControlOrganization (“CDSCO”), National Institute of Health Sciences (“NIHS”),Ministry of Food and Drug Safety (“MFDS”) and the like), andderivatives, isomers, precursors, and/or enantiomers thereof, atresearch and/or production scale quantities.

In still further embodiments, the present disclosure provides nat-and/or ent-steroid compositions that are medically useful by themselvesor as incorporated into medicinal formulations to treat, prevent, and/orcure, a range of diseases and medical conditions related to, but notlimited to, cancers, tumors, and other hyper-proliferative diseases,cardiovascular diseases, inflammation, pain, autoimmune diseases anddisorders (e.g., Crohn's disease, ulcerative colitis, psoriasis,psoriatic arthritis, juvenile arthritis and ankylosing spondilitis,autoimmune diabetes, multiple sclerosis, systemic lupus erythematosus,rheumatoid spondylitis, gouty arthritis, allergy, autoimmune uveitis,nephrotic syndrome, multisystem autoimmune diseases, autoimmune hearingloss, adult respiratory distress syndrome, shock lung, chronic pulmonaryinflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis,silicosis, idiopathic interstitial lung disease, chronic obstructivepulmonary disease, asthma, restenosis, spondyloarthropathies, Reiter'ssyndrome, autoimmune hepatitis, inflammatory skin disorders, vasculitisof large vessels, medium vessels or small vessels, endometriosis,prostatitis and Sjogren's syndrome, and the like), and brain injuries,including trauma both physical and chemically induced, among otherdiseases, and as import chemical precursors for additional steroidderivatives. In still other embodiments, the present disclosure providessteroid compositions and steroid based compositions useful forregulating growth and or reproductive function/dysfunction in anorganism (e.g., estrogen, progesterone, testosterone, pregnenolone, andthe like).

The present disclosure further contemplates that certain nat- and/orent-steroidal compositions provided herein are useful analytes (ligands)in studies to understand steroid-membrane receptor interactions from amechanistic as well as an applied drug discovery and development pointof view. More particularly, it is contemplated that the presentcompositions are useful in studies to differentiate steroid-membranereceptor interactions from other intercellular and intracellularsteroid-receptor interactions (e.g., steroid-nuclear receptorinteractions). Even more particularly, certain steroid compositions ofthe present disclosure are useful in mechanistic studies aimed atdistinguishing the direct effects of steroid-membrane receptorinteraction(s) (e.g., binding the receptor of interest) from indirecteffects resulting from steroid caused membrane perturbation(s) (e.g.,alteration of the membrane environment).

The novel ent-steroids of the present disclosure (e.g., mirror images ofnaturally occurring steroids) are useful tools for distinguishingbetween various actions of steroids in membranes and/orreceptor-mediated signaling pathways.

While the present disclosure is not limited to any particularmechanism(s) or mode(s) of action, it is contemplated that the nat- andent-steroids made using the methods of the present disclosure can beused in studies/assays designed to differentiate the direct and indirecteffects of steroids on membrane receptor function. Enantiomeric steroids(i.e., the nat- and ent-steroids) are mirror images of one another thatshare identical physicochemical properties. It is further contemplated,that since steroid receptor binding pockets are typically well-definedand structurally maintained, one enantiomeric ligand (e.g., thenat-steroid enantiomer) will preferentially bind to the receptor incomparison to the other enantiomer (e.g., the ent-steroid enantiomer).It is understood that ligand-receptor binding (in the case of steroidenantiomers) is enantioselective (i.e., one enantiomer will bind moreeffectively than the other enantiomer). Excluding the steroid-receptors,the remaining membrane constituents (e.g., lipids (phospholipids,glycolipids, and sterols), proteins, and carbohydrates) exist in adynamic environment. It is further contemplated that the steroid'sphysiochemical properties will be more important in affecting themembrane than its enantiomeric configuration (i.e., nat- versus ent-).

In other words, both nat- and ent-steroids are contemplated to havenearly equivalent (non-enantioselective) effects on the membrane.Accordingly, the direct steroid-receptor binding effects as well as theindirect effects of steroid caused membrane perturbation should bedistinguishable by measuring the differences in steroid-receptorenantioselectivity. (See, Biellmann, J. F., Chem. Rev., 103, 2019-2033[2003]; Covey, D. F., Steroids, 74(4):577-585 [2009]). Nevertheless,certain ent-steroids are, or nearly are, as effective as theirnat-steroid counterpart at modulating protein function.

Various compositions of the present disclosure are useful for modulating(e.g., increasing or decreasing the activity or function thereof)particular membrane protein targets (e.g., steroid receptors). Thoseskilled in the art will appreciate that certain steroidal compositionsproduced according to the present disclosure can be characterized and/orclassified according to the rapid non-genomic actions of steroids andthe Mannheim Classification. (See, Falkenstein, E., et al., J. Clin.Endocrinol. Metab., 85, 2072-2075 [2000]; Losel, R., and Wehling, M.,Nat. Rev. Mol. Cell Biol., 4, 46-56 [2003]; and Wehling, M., and Losel,R., J. Steroid Biochem. Mol. Biol., 102, 180-183 [2006]).

The nat- and ent-steroidal compositions of the present disclosure arenot contemplated to be limited to interactions only with target steroidmembrane receptors, indeed, other biological macro-/molecules are knownto interact (e.g., bind) with steroids including, but not limited to,enzymes, receptors, transporters, antibodies, peptides (e.g., poly-,proteins), lipids, saccharides (e.g., mono-, di-, oligo-,poly-saccharides), nucleotides (e.g., mono-, di-, oligo-,poly-nucleotides), biomimetics, and the like.

E. COMPOSITIONS

In at least one aspect, the present disclosure includes compositionscomprising a compound described herein or a salt thereof. In certainembodiments, the composition comprises a compound of Formula (I) or asalt thereof. In certain embodiments, the composition comprises acompound of Formula (IA) or a salt thereof. In certain embodiments, thecomposition comprises a compound of Formula (IB) or a salt thereof. Incertain embodiments, the composition comprises a compound of Formula(IC) or a salt thereof. In certain embodiments, the compositioncomprises a compound of Formula (ID) or a salt thereof. In certainembodiments, the composition comprises a compound of Formula (II) or asalt thereof.

In certain embodiments, the composition comprises one or moreconventional pharmaceutically acceptable carriers. Pharmaceuticallyacceptable carriers include, without limitation, a non-toxic, inertsolid, semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. Some examples of materials which canserve as pharmaceutically acceptable carriers are sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols such as propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations. Formulation of drugs is generally discussedin, for example, Hoover, J., Remington's Pharmaceutical Sciences (MackPublishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and DrugDelivery Systems (Lippincott Williams & Wilkins, 2005).

In at least one aspect, the present disclosure includes pharmaceuticalcompositions comprising a therapeutically effective amount of a compounddescribed herein in combination with one or more pharmaceuticallyacceptable carriers. In certain embodiments, the pharmaceuticalcompositions comprise a compound of formula (I) or a salt thereofformulated together with one or more pharmaceutically acceptablecarriers. In certain embodiments, the pharmaceutical compositionscomprise a compound of formula (IA) or a salt thereof formulatedtogether with one or more pharmaceutically acceptable carriers. Incertain embodiments, the pharmaceutical compositions comprise a compoundof formula (IB) or a salt thereof formulated together with one or morepharmaceutically acceptable carriers. In certain embodiments, thepharmaceutical compositions comprise a compound of formula (IC) or asalt thereof formulated together with one or more pharmaceuticallyacceptable carriers. In certain embodiments, the pharmaceuticalcompositions comprise a compound of formula (ID) or a salt thereofformulated together with one or more pharmaceutically acceptablecarriers. In certain embodiments, the pharmaceutical compositionscomprise a compound of formula (II) or a salt thereof formulatedtogether with one or more pharmaceutically acceptable carriers.

The pharmaceutical compositions may be formulated for any route ofadministration. The pharmaceutical compositions can be administered tohumans and other animals orally, nasally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), or bucally. The term “parenterally”, asused herein, refers to modes of administration which includeintravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous,intraarticular injection and infusion.

In certain embodiments, the pharmaceutical compositions are formulatedfor oral administration in solid or liquid form.

In certain embodiments, the pharmaceutical composition is a solid dosageform for oral administration. Solid dosage forms for oral administrationinclude capsules, tablets, pills, powders, and granules. In certainembodiments, the pharmaceutical composition includes, for example,lactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol. In certain embodiments, the pharmaceuticalcomposition is tableted or encapsulated for convenient administration.In certain embodiments, such capsules or tablets contain acontrolled-release formulation, as can be provided in, for example, adispersion of the compound or salt in hydroxypropylmethyl cellulose. Inthe case of capsules, tablets, and pills, the dosage forms also cancomprise buffering agents, such as sodium citrate, or magnesium orcalcium carbonate or bicarbonate. Tablets and pills additionally can beprepared with enteric coatings.

In certain embodiments, the pharmaceutical composition is a liquiddosage form for oral administration. Liquid dosage forms for oraladministration include, for example, pharmaceutically acceptableemulsions (including both oil-in-water and water-in-oil emulsions),solutions (including both aqueous and non-aqueous solutions),suspensions (including both aqueous and non-aqueous suspensions),syrups, and elixirs. In certain embodiments, the liquid dosage formscontain inert diluents commonly used in the art such as, for example,water or other solvents, solubilizing agents and emulsifiers such asethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof. In addition, in certain embodiments, oralcompositions, also include wetting, emulsifying, suspending, flavoring(e.g., sweetening), and/or perfuming agents.

In certain embodiments, the pharmaceutical composition is for parenteraladministration. In certain embodiments, formulations for parenteraladministration are prepared from sterile powders or granules having oneor more of the carriers or excipients mentioned for use in theformulations for oral administration. In certain embodiments, a compoundor salt thereof is dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. In certainembodiments, the pH is adjusted, if necessary, with a suitable acid,base, or buffer.

Parenteral administration includes subcutaneous injections, intravenousinjections, intramuscular injections, intrasternal injections, andinfusion. Injectable preparations (e.g., sterile injectable aqueous oroleaginous suspensions) can be formulated according to the known artusing suitable dispersing, wetting agents, and/or suspending agents.Acceptable vehicles and solvents include, for example, water,1,3-butanediol, Ringer's solution, isotonic sodium chloride solution,bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids(e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic andnon-ionic detergents), and/or polyethylene glycols.

In certain embodiments, the pharmaceutical composition is for rectal orvaginal administration. Compositions for rectal or vaginaladministration are preferably suppositories that can be prepared by, forexample, mixing a compound or salt thereof with a suitable nonirritatingcarrier or excipient that is solid at ordinary room temperatures, butliquid at body temperature. Suitable carriers or excipients include, forexample, cocoa butter; synthetic mono-, di-, or triglycerides, fattyacids, and/or polyethylene glycols.

Topical administration includes the use of transdermal administration,such as transdermal patches or iontophoresis devices.

Other carriers and modes of administration known in the pharmaceuticalart also may be used.

In certain embodiments, the compounds are used in the form ofpharmaceutically acceptable salts or esters, or amides derived frominorganic or organic acids. In certain embodiments, pharmaceuticallyacceptable salts are those salts that are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humansand lower animals without undue toxicity, irritation, allergic response,and the like, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well-known in the field. The saltscan be prepared in situ during the final isolation and purification ofthe present compounds or separately by, for example, reacting a freebase function with a suitable organic acid.

Representative pharmaceutically acceptable salts include, but are notlimited to, acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

In certain embodiments, pharmaceutically acceptable acid addition saltsof the compounds of Formula (I), (IA), (IB), (IC), (ID), or (II) areprepared from an inorganic or organic acid. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude inorganic acids such as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and organic acids such as aceticacid, oxalic acid, maleic acid, succinic acid, tartaric acid, and citricacid. In certain embodiments, a weak acid, including, but not limitedto, tartaric acid, lactic acid, acetic acid, propionic acid, citricacid, malic acid, and the like, can be employed to form pharmaceuticallyacceptable acid addition salt.

In certain embodiments, pharmaceutically acceptable base addition saltsof the compounds of Formula (I), (IA), (IB), (IC), (ID), or (II)include, for example, metallic salts and organic salts. In certainembodiments, pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas lithium, sodium, potassium, calcium, magnesium, and aluminum salts,and the like, and nontoxic quaternary ammonia and amine cationsincluding ammonium, tetramethylammonium, tetraethylammonium,methylammonium, dimethylammonium, trimethylammonium, triethylammonium,diethylammonium, ethylammonium and the like. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

In certain embodiments, at least 50% of the composition comprises acompound of Formula (I), (IA), (IB), (IC), (ID), (II), or a saltthereof. In certain embodiments, at least 60% of the compositioncomprises a compound of Formula (I), (IA), (IB), (IC), (ID), (II), or asalt thereof. In certain embodiments, at least 70% of the compositioncomprises a compound of Formula (I), (IA), (IB), (IC), (ID), (II), or asalt thereof. In certain embodiments, at least 80% of the compositioncomprises a compound of Formula (I), (IA), (IB), (IC), (ID), (II), or asalt thereof. In certain embodiments, at least 90% of the compositioncomprises a compound of Formula (I), (IA), (IB), (IC), (ID), (II), orsalt thereof. In certain embodiments, at least 95% of the compositioncomprises a compound of Formula (I), (IA), (IB), (IC), (ID), (II), or asalt thereof.

In one aspect, the present disclosure includes a pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltdescribed herein and a pharmaceutically acceptable excipient.

F. ADDITIONAL FORMULATION, ADMINISTRATION, AND DOSING CONSIDERATIONS

The practice of the present disclosure will employ, unless otherwiseindicated, conventional techniques of preparing pharmaceuticalformulations as well as drug delivery and dosing techniques which arewell known in the art.

Generally speaking, the methods and compositions of the presentdisclosure provides treatments suitable for populations of cells (e.g.,tissues, organs, structures, and the like) in a subject (e.g., animal orhuman), in order to confer a medicinal or therapeutic benefit to thatpopulation, by the administration of an effective dose of the one ormore of compound described herein. In some cases, theplasma/blood/serum/urine or otherwise provided concentrations of theadministered compounds is less than or greater than about 100 μM, 10 μM,1 μM, 500 nM, 100 nM, 10 nM, or even 1 nM (i.e., from about 0.1 nM toabout 1 nM), however, the physician will be able to determine effectivedosing concentrations, patterns, and administration routes uponconsideration to the subject's age, sex, weight, health status, andother relevant physical, biochemical, genetic, factors, conditions, andthe like.

In some embodiments, the concentration of one or more of the compoundsprovided in the pharmaceutical compositions of the present disclosure isless than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%,16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%,0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%,0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In yet some other embodiments, the concentration of one or more of thecompounds of the present disclosure is greater than 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%,15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%,10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%,7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%,4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%,2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w,w/v, or v/v.

In still some other embodiments, the concentration of one or more of thecompounds of the present disclosure is in the range from approximately0.0001% to approximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v. v/v.

In some embodiments, the concentration of one or more of the compoundsof the present disclosure is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some other embodiments, the amount of one or more of the compounds ofthe present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g,3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g,0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g,0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g,0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more of the compounds of thepresent disclosure is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g,0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g,0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g,0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g,0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g,0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g,0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

Other embodiments provide, amounts of one or more of the compounds ofthe present disclosure in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

More particularly, one or more compositions of the present disclosuremay be administered in any suitable amount(s), and in the orderdisclosed herein. In some embodiments, a first composition (first agent)is administered to a subject within a range of about 0.1 mg/kg-50 mg/kgper day, such as about, less than about, or more than about, 1 mg/kg, 2mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40mg/kg, 45 mg/kg, or 50 mg/kg per day. In some embodiments, a compositionis administered to a subject within a range of about 0.1 mg/kg-400 mg/kgper week, such as about, less than about, or more than about 1 mg/kg, 5mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40mg/kg, 45 mg/kg, 50 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg,300 mg/kg, 350 mg/kg, or 400 mg/kg per week. In some embodiments, afirst agent is administered to a subject within a range of about 0.1mg/kg-1500 mg/kg per month, such as about, less than about, or more thanabout 50 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg,350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg,or 1000 mg/kg per month. In some embodiments, a first agent isadministered to a subject within a range of about 0.1 mg/m²-200 mg/m²per week, such as about, less than about, or more than about 5 mg/m², 10mg/m², 15 mg/m², 20 mg/m², 25 mg/m², 30 mg/m², 35 mg/m², 40 mg/m², 45mg/m², 50 mg/m², 55 mg/m², 60 mg/m², 65 mg/m², 70 mg/m², 75 mg/m², 100mg/m m², 125 mg/m², 150 mg/m², 175 mg/m², or 200 mg/m² per week. Thetarget dose may be administered in a single dose. Alternatively, thetarget dose may be administered in about or more than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, ormore doses. For example, a dose of about 20 mg/kg per week may bedelivered weekly at a dose of about 20 mg/kg, or may be delivered at adose of about 6.67 mg/kg administered on each of three days over thecourse of the week, which days may or may not be consecutive. Theadministration schedule may be repeated according to any prescribedregimen, including any administration schedule described herein. In someembodiments, a first agent is administered to a subject in the range ofabout 0.1 mg/m²-500 mg/m m², such as about, less than about, or morethan about 5 mg/m², 10 mg/m², 15 mg/m², 20 mg/m m², 25 mg/m², 30 mg/m²,35 mg/m m², 40 mg/m m², 45 mg/m², 50 mg/m², 55 mg/m², 60 mg/m², 65mg/m², 70 mg/m², 75 mg/m², 100 mg/m², 130 mg/m², 135 mg/m², 155 mg/m²,175 mg/m², 200 mg/m², 225 mg/m², 250 mg/m², 300 mg/m², 350 mg/m², 400mg/m², 420 mg/m m², 450 mg/m², or 500 mg/m m².

The compositions disclosed herein may be administered in one dose ormultiple dosages. Methods of determining the most effective means anddosage of administration are well known to those of skill in the art andwill vary with the composition used for therapy, the purpose of thetherapy, the target cell or tissue being treated, and the subject beingtreated. Single or multiple administrations (e.g., about or more thanabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 25, 30, or more doses) can be carried out with the dose level andpattern being selected by the treating physician. It is known in the artthat due to intersubject variability in compound pharmacokinetics,individualization of dosing regimen is necessary for optimal therapy.Dosing for composition of the invention may be found by routineexperimentation in light of the instant disclosure and one's skill inthe art.

A first agent composition of the invention may be mixed with one or moreother drug substance(s) (e.g., a second agent, a third agents, etc.) ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the one or more other drugsubstance(s).

Administration of any of the compounds disclosed herein may be achievedby means standard in the art, and may include the use of a singlecompound or a mixture of two or more compounds, their enantiomers ordiastereomers, or pharmaceutically acceptable salts, and otherpharmaceutical preparations thereof.

Administration of the compounds disclosed herein can be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topical(e.g., transdermal application), rectal administration, via localdelivery by catheter or stent or through inhalation. Compounds can alsobe administered intraadiposally or intrathecally. An effective amount ofan inhibitor of the invention may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, including rectal, buccal, intranasal andtransdermal routes, by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, as an inhalant, or via an impregnated or coateddevice such as a stent, for example, or an artery-inserted cylindricalpolymer. Sequential administration of a first composition and/or anyadditional therapeutic agent can be effected by any appropriate route asnoted above and including, but not limited to, oral routes, intravenousroutes, intramuscular routes, and direct absorption through mucousmembrane tissues. The therapeutic agents can be administered by the sameroute or by different routes. For example, a first composition(therapeutic agent) of the combination selected may be administered byintravenous injection while the other therapeutic agents of thecombination may be administered orally. Alternatively, for example, alltherapeutic agents may be administered orally or all therapeutic agentsmay be administered by intravenous injection. Methods of administeringthe compounds of the invention may be by metered dose or by one or morecontrolled release devices.

Additionally, it is to be noted that, similar to the approachesdescribed in the fields of medicinal and pharmaceutical chemistry, asuitable pharmaceutical preparation may also include, optionally, inaddition to one or more compounds disclosed herein, other agents,including, but not limited to, excipients, diluents, extenders,stabilizers, colors, flavors, formulating agents (e.g., talc, minerals,and other press-able powders), encapsulating agents (e.g., entericcoatings), antioxidants, preservatives, sterile aqueous solutions,buffers, sugars, and the like, as are generally known and accepted.

Additionally, subject pharmaceutical compositions may, for example, bein a form suitable for oral administration as a tablet, capsule, pill,powder, sustained release formulations, solution, suspension, forparenteral injection as a sterile solution, suspension or emulsion, fortopical administration as an ointment or cream or for rectaladministration as a suppository. The pharmaceutical composition may bein unit dosage forms suitable for single administration of precisedosages. The pharmaceutical composition will include a conventionalpharmaceutical carrier or excipient and an inhibitor according to theinvention as an active ingredient. In addition, it may include othermedicinal or pharmaceutical agents, carriers, adjuvants, etc.

Generally speaking, the compounds disclosed herein may be prepared bymeans standard in the art. A number of standard text are known in theart regarding preparation and formulation considerations. (See e.g.,Remington's Pharmaceutical Sciences).

In other embodiments, one or more additional small molecule drug and/orbiological agents may be preferentially combined with the one or morecompounds disclosed herein to achieve a beneficial, or even synergistic,outcome in the subject.

The present compounds are suitable, for example, in treating subjectssuffering from trauma, chronic degenerative diseases or acute diseasesuch as induced by an ischemic attack. Specific examples includeAlzheimer's disease, Parkinson's disease, stroke, ischemia, heart attackor angioplasty, or brain or spinal cord trauma, hypoglycemia, anoxia,burns or surgeries that result in the loss of nutrient flow to thetissues. Other diseases that may be treatable with compounds of thecurrent invention include, but are not limited to: heart disease,including, but not limited to, restenosis, atherosclerosis, myocardialinfarction, ophthalmologic diseases, including, but not limited to,macular degeneration, lens or retinal degeneration, formation ofcataracts and glaucoma, alcoholism, alcohol withdrawal, drug-inducedseizures vascular occlusion, epilepsy, cerebral vascular hemorrhage,hemorrhage; environmental excitotoxins, dementias, drug-induced braindamage and other systemic or acute degenerative diseases characterizedby necrotic or apoptotic cell death. To-date, there are no known curesand few therapies that slow the progression of many diseases.

Certain embodiments of the present disclosure may further be applied tothe procedure of tissue transplantation, prior, during or after removalor reperfusion of cells, tissues or organs or during storage of thecells, tissues or organs and is applicable to any of the cells in thebody.

In some embodiments, the subject is a human in need of treatment forcancer, or a precancerous condition or lesion. Subjects that can betreated with a compound or pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof, according to themethods of this disclosure include, for example, subjects that have beendiagnosed as having renal cell carcinoma, unresectable hepatocellularcarcinoma, or thyroid carcinoma, breast cancer such as a ductalcarcinoma in duct tissue in a mammary gland, medullary carcinomas,colloid carcinomas, tubular carcinomas, and inflammatory breast cancer;ovarian cancer, including epithelial ovarian tumors such asadenocarcinoma in the ovary and an adenocarcinoma that has migrated fromthe ovary into the abdominal cavity; uterine cancer; cervical cancersuch as adenocarcinoma in the cervix epithelial including squamous cellcarcinoma and adenocarcinomas; prostate cancer, such as a prostatecancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer such asepitheloid carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus(HPV) and cervical cancer; central nervous system cancers (CNS) such asprimary brain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMullerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer, and the like.

Detection, monitoring, and rating of various cancers in a human arefurther described in Cancer Facts and Figures 2001, American CancerSociety, New York, N.Y., and International Patent Application WO01/24684. Accordingly, a physician can use standard tests to determinethe efficacy of the various embodiments of the inventive compositionsand methods in treating cancer. However, in addition to tumor size andspread, the physician also may consider quality of life and survival ofthe subject in evaluating efficacy of treatment.

Certain compounds disclosed herein are also useful as co-therapeuticcompounds for use in combination with other drug substances, forexample, but not limited to, agents such as anti-inflammatory,bronchodilatory or antihistamine drug substances, particularly in thetreatment of obstructive or inflammatory airways diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. Suitable antihistamine drugsubstances include cetirizine hydrochloride, acetaminophen, clemastinefumarate, promethazine, loratidine, desloratadine, diphenhydramine andfexofenadine hydrochloride, activastine, astemizole, azelastine,ebastine, epinastine, mizolastine and tefenadine, and the like. Otheruseful combinations of compounds of the invention with anti-inflammatorydrugs are those with antagonists of chemokine receptors, e.g., CCR-1,CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1,CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such asantagonists SC-351 125, SCH-55700 and SCH-D, antagonists such asTAK-770, and CCR-5 antagonists. The compounds of the invention may beformulated or administered in conjunction with other agents that act torelieve the symptoms of inflammatory conditions such asencephalomyelitis, asthma, and the other diseases described herein.These agents include non-steroidal anti-inflammatory drugs (NSAIDs)(e.g., acetylsalicylic acid, ibuprofen, naproxen, indomethacin,nabumetone, tolmetin, and the like). Corticosteroids are used to reduceinflammation and suppress activity of the immune system.

The activity of the compounds disclosed herein may be determined bymeans standard in the art.

The compounds, compositions, and methods described herein will be betterunderstood by reference to the following examples, which are included asan illustration of and not a limitation upon the scope of the invention.

G. EXEMPLARY EMBODIMENTS

In one aspect, the present disclosure provides a steroid compositionaccording to a method for the present disclosure. In certainembodiments, the steroid is an ent-steroid. In some such embodiments,the ent-steroid has a structure corresponding to Formula (II). In somesuch embodiments, the ent-steroid is Compound 39.

In another aspect, the present disclosure provides a method for makingent-steroids according to the present disclosure.

In yet another aspect, the present disclosure provides a steroidcomposition according to a method for the present disclosure. In certainembodiments, the steroid is a nat-steroid. In some such embodiments, thenat-steroid is Compound 205b.

It will be readily apparent to those skilled in the art that othersuitable modifications and adaptations of the compositions and methodsof the invention described herein are obvious and may be made usingsuitable equivalents without departing from the scope of the inventionor the embodiments disclosed herein.

Having now described the present invention in detail, the same will bemore clearly understood by reference to the following examples, whichare included for purposes of illustration only and are not intended tolimit the invention.

H. EXAMPLES

General Materials and Methods.

1. Reagents and Solvents.

All reactions were conducted in flame-dried glassware under a nitrogenatmosphere with dry solvents, unless otherwise noted. All reagents andstarting materials were purchased from commercial sources and used assupplied, unless otherwise indicated.

Anhydrous diethyl ether (Et₂O), dimethylformamide (DMF), tetrahydrofuran(THF), toluene (PhMe), methylene chloride (CH₂Cl₂) were obtained by theGlass Contour Solvent Purification System. Anhydrous methanol (MeOH) waspurchased in a Sure-Seal™ bottle from Sigma-Aldrich. Solutions of n-BuLi(2.5 M in hexanes) were purchased from Sigma-Aldrich and titratedagainst N-benzylbenzamide in accordance with the procedure reported byBurchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542,281-283.

For flash column chromatography, HPLC grade solvents were used withoutfurther purification.

2. Reaction Set-Up and Purification

Reaction mixtures were magnetically stirred and their progress wasmonitored by thin layer chromatography (TLC) on EMD TLC silica gel 60F₂₅₄ glass-backed plates. Compounds were visualized by UV-light (254 nm)or an aqueous solution of phosphomolybdic acid, ceric sulfate, andsulfuric acid (EMD Millipore, Billerica, Mass., USA).

Purification of crude isolates was achieved by flash columnchromatography on a BIOTAGE ISOLERA ONE Automated Liquid ChromatographySystem using silica gel cartridges (Biotage, Charlotte, N.C., USA) orperformed using a forced flow of the indicated solvent system on SORBENTTECHNOLOGIES silica gel 60 Å (40-63 μm particle size). Concentration ofreaction product solutions and chromatography fractions was accomplishedby rotary evaporation at 30-35° C. under the appropriate pressure,followed by concentration at room temperature on a vacuum pump (approx.0-1 mbar). Yields refer to chromatographically purified andspectroscopically pure compounds, unless otherwise indicated.

3. Compound Characterization

¹H NMR data were recorded on Bruker Avance III 500 and 600 MHzspectrometer (TBI probe). ¹³C NMR data were recorded at 125 MHz and 150MHz on Bruker Avance III 500 and 600 MHz spectrometer (TBI probe).Infrared spectra were recorded on a JASCO FT/IRM4100 Fourier TransformInfrared Spectrometer. Optical rotations were measured with a JASCODIP-370 and JASCO P-2000 polarimeter. HRMS (ESI or EI) analyses wereperformed at the Mass Spectrometry Laboratory of University of Illinoisat Urbana-Champaign. All compounds purified by chromatography weresufficiently pure for use in further experiments, unless indicatedotherwise.

Optical rotations (a) were obtained on a JASCO-P-2000 polarimeterequipped with tungsten-halogen lamp (WI) and interface filter set to 589nm, using a sample cell with a pathlength of 100 nm. Specific rotationsare reported as: [α]₅₈₉ ^(T(° C.)) (c, solvent) and are based on theequation [α]₅₈₉ ^(T(° C.))=(100·α)/(l·c), where the concentration (c) isreported as g/100 ml and the pathlength (l) in decimeters.

Example 1

General Synthetic Procedures, Preparation of Reaction Intermediates

(R)-epichlorohydrin 5 and (S)-epichlorohydrin ent-5 were purchased fromChem Impex. Alkyne 7, alkyne 19, alkyne 22, and anhydrous methanol(MeOH) were purchased from Sigma-Aldrich, St. Louis, Mo., USA.Chloroform (CHCl₃) and bromoform (CHBr₃) were purchased from Alfa Aesar,Tewksbury, Mass., USA. Titanium isopropoxide (Ti(Oi-Pr)₄), andnitromethane (MeNO₂) were purchased from Acros Organics (Pittsburgh,Pa., USA), and titanium isopropoxide was distilled before use.

The hydrindane products of Ti-mediated annulation (alkene isomers) wereused in subsequent steps as mixtures (the steroidal end products of thesynthesis sequence were easily separated from byproducts generated fromthe minor “endo” diene isomer). For characterization of the majorisomers formed from Ti-mediated annulation, a small amount of eachmixture (<50 mg) was purified by HPLC to obtain analytical samples.(See, the trans-fused hydrindanes: 8, ent-8, 14, 17, 20, 23, 26, 29, 32,and S16).

Abbreviations

KOt-Bu: potassium tert-butoxide; TEBAC: benzyltriethylammonium chloride;MeNO₂: nitromethane, i-PrOH: isopropanol; MeOH: methanol.

Where yields are given, the data refers to chromatographically andspectroscopically (¹H NMR) homogeneous materials, unless otherwisestated.

1A. Epoxide S2 and Chlorohydrin S1

This Example describes the production of intermediates epoxide S2 andchlorohydrin S1 used in subsequent reactions.

To a stirring solution of phenyl propargyl ether (0.50 g, 3.8 mmol, 1.0equiv) in 5 mL THF at −78° C. under N₂ atmosphere was added n-BuLi (2.5M in hexanes, 1.5 mL, 3.8 mmol, 1.0 equiv) dropwise. The resultingsolution was stirred for 1 h at −78° C., and (R)-epichlorohydrin 5 (0.35g, 3.8 mmol, 1.0 equiv) was added dropwise. The resulting mixture wasslowly warmed to rt and stirred overnight (approx. 12 h), then 20 mLsat. NH₄Cl (aq) was added. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were dried over anhydrous MgSO₄, filtered through acoarse fritted glass funnel, and the filtrate was concentrated in vacuo.Purification of the crude product by flash column chromatographyafforded 0.12 g of epoxide S2 as a yellow film (17%) and 0.26 gchlorohydrin S1 as a yellow oil (31%).

1B. Enyne 6

This Example describes the production of intermediate enyne 6 used insubsequent reactions.

To a stirring solution of phenyl propargyl ether (18.2 g, 138 mmol, 1.5equiv) in 500 mL THF at −78° C. under N₂ atmosphere was added n-BuLi(2.5 M in hexanes, 50.0 mL, 130 mmol, 1.4 equiv) dropwise. The resultingsolution was stirred for 15 min at −78° C., and then BF₃.Et₂O (21.3 g,150 mmol, 1.7 equiv) and (R)-epichlorohydrin 5 (8.3 g, 89 mmol, 1.0equiv) were added dropwise. The resulting mixture was stirred for anadditional 1 h at −78° C., warmed to 0° C., and then 100 mL sat. NH₄Cl(aq) was added. The organic layer was separated, and the aqueous layerwas extracted with Et₂O (200 mL×3). The combined organic layers weredried over anhydrous MgSO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo. The crude oil wasdissolved in hexanes, and then passed through a pad of silica gel using85% hexanes:15% ethyl acetate as the eluent to afford 10.4 g of thecrude product (yellow oil), that was used in the next step withoutfurther purification.

To a stirring solution of the above crude product (10.4 g) in 1.1 L Et₂Ounder N₂ atmosphere at rt was added KOt-Bu (4.6 g, 41 mmol). Theresulting yellow suspension was stirred until the reaction was judged tobe complete by TLC analysis. 500 mL sat. NaHCO₃ (aq) was added to thereaction mixture, and the organic layer was separated. The aqueous layerwas extracted with Et₂O (200 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 8.3 g ofthe crude epoxide S2 (yellow oil), that was used in the next stepwithout further purification.

To a stirring solution of 60% weight of the above epoxide S2 (5.0 g) in75 mL THF under N₂ atmosphere at −78° C. was added CuI (1.0 g, 5.3 mmol)followed by isopropenyl magnesium bromide (0.50 M in THF, 74 mL, 37mmol). The resulting yellow suspension was stirred for 1 h at −78° C.,warmed to rt, and then stirred until the reaction was judged to becomplete by TLC analysis. The reaction was quenched by adding 100 mLsat. NH₄Cl (aq) to the reaction mixture.

The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product bySiO₂ flash column chromatography using 20% ethyl acetate: 80% hexanes asthe eluent afforded 4.8 g of the compound enyne 6 as a pale yellow oil(39% over 3 steps).

1C. Epoxide 42

This Example describes the production of intermediate epoxide 42 used insubsequent reactions.

Briefly, n-BuLi (2.5 M in hexanes, 0.15 L, 0.38 mol, 1.0 equiv) wasadded dropwise to a stirring solution of phenyl propargyl ether (50.0 g,0.38 mol, 1.0 equiv) in 500 mL THF at −78° C. under N₂ atmosphere. Theresulting solution was stirred for 0.5 h at −78° C., and(S)-epichlorohydrin ent-5 (42.0 g, 0.46 mol, 1.2 equiv) was addeddropwise. The resulting mixture was slowly warmed to rt and stirredovernight (approx. 12 h), then 300 mL sat. NH₄Cl (aq) was added. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (300 mL×3). The combined organic layers were dried overanhydrous MgSO₄, filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo to afford 35 g of the crude product.The crude product containing ent-S1 and epoxide 42 (ent-S1:42=2.4:1based on the crude product analysis by ¹H NMR) was used in the next stepwithout further purification.

To a stirring solution of 80% weight of the above crude product (28 g)in 2.5 L Et₂O under N₂ atmosphere at rt was added KOt-Bu (9.3 g, 0.083mol). The resulting yellow suspension was stirred until the reaction wasjudged to be complete by TLC analysis. 500 mL sat. NaHCO₃ (aq) was addedto the reaction mixture, and the organic layer was separated. Thecombined organic layers were dried over anhydrous MgSO₄, filteredthrough a coarse fritted glass funnel, and the filtrate was concentratedin vacuo. Purification of the crude product by SiO₂ flash columnchromatography using 20% ethyl acetate: 80% hexanes as the eluentafforded 24.9 g of the compound epoxide 42 as a pale yellow oil (44%over 2 steps).

1D. S3

This Example describes the production of intermediate S3 used insubsequent reactions.

To a stirring suspension of Mg turnings (0.40 g, 17 mmol, 1.3 equiv) in20 mL THF under N₂ atmosphere at rt was added 1,2-dibromoethane (0.29 g,1.53 mmol, 0.12 equiv) dropwise. The resulting mixture was heated with aheat gun for approximately 1 min. Once the reaction was initiated,2-bromobut-1-ene (2.1 g, 15.3 mmol, 1.2 equiv) was added dropwise whilemaintaining gentle reflux. After the addition, the resulting yellowsuspension was further refluxed for an additional 1 h and cooled to rt.The resulting Grignard solution was transferred by syringe to a stirringsuspension of epoxide 42 (2.4 g, 13 mmol, 1.0 equiv) and CuI (0.48 g,2.5 mmol, 0.19 equiv) in 50 mL THF under N₂ atmosphere at −78° C. Theresulting yellow suspension was stirred for 1 h at −78° C., warmed tort, and then stirred until the reaction was judged to be complete by TLCanalysis. The reaction was quenched by adding 100 mL of sat. NH₄Cl (aq)to the reaction mixture. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were dried over anhydrous MgSO₄, filtered through acoarse fritted glass funnel, and the filtrate was concentrated in vacuo.Purification of the crude product by SiO₂ flash column chromatographyusing 20% ethyl acetate:80% hexanes as the eluent afforded 2.4 g of thetitle compound S3 as a yellow oil (77%).

1E. S4

This Example describes the production of intermediate S4 used insubsequent reactions.

To a stirring suspension of Mg turnings (0.27 g, 11.2 mmol, 1.3 equiv)in 15 mL THF under N₂ atmosphere at rt was added 1,2-dibromoethane (0.20g, 1.1 mmol) dropwise. The resulting mixture was heated with a heat gunfor approximately 1 min. Once the reaction was initiated,(2-bromoallyl)benzene (2.0 g, 10.2 mmol) was added dropwise whilemaintaining gentle reflux. After the addition, the resulting yellowsuspension was further refluxed for an additional 1 h and cooled to rt.The resulting Grignard solution was transferred using syringe to astirring suspension of epoxide 42 (1.6 g, 8.5 mmol) and CuI (0.32 g, 1.7mmol, 0.20 equiv) in 20 mL THF under N₂ atmosphere at −78° C. Theresulting yellow suspension was stirred for 1 h at −78° C., warmed tort, and then stirred until the reaction was judged to be complete by TLCanalysis. The reaction was quenched by adding 80 mL of sat. NH₄Cl (aq)to the reaction mixture. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (80 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered through acoarse fritted glass funnel, and the filtrate was concentrated in vacuo.Purification of the crude product by SiO₂ flash column chromatographyusing 20% ethyl acetate: 80% hexanes as the eluent afforded 2.3 g ofcompound S4 as a yellow oil (88%).

1F. Enyne (ent-6)

This Example describes the production of intermediate enyne (ent-6) usedin subsequent reactions.

To a stirring solution of phenyl propargyl ether (16 g, 0.12 mol, 2.0equiv) in 200 mL THE at −78° C. under N₂ atmosphere was added n-BuLi(2.5 M in hexanes, 41 mL, 0.10 mol, 1.7 equiv) dropwise. The resultingsolution was stirred for 15 min at −78° C., and then BF₃.THF (15 g, 0.12mol, 2.0 equiv) and (S)-epichlorohydrin ent-5 (5.7 g, 61 mmol, 1.0equiv) were sequentially added dropwise. The resulting mixture wasstirred for an additional 1 h at −78° C., warmed to 0° C., and then 100mL brine was added. The organic layer was separated, and the aqueouslayer was extracted with Et₂O (200 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered through a coarse frittedglass funnel, and the filtrate was concentrated in vacuo. The crude oilwas dissolved in hexanes, and then eluted through a pad of silica gelusing 15% ethyl acetate:85% hexanes as the eluent to afford 12 g of thecrude ent-S1 (yellow oil), that was used in the next step withoutfurther purification.

To a stirring solution of the above crude product (12 g) in 1.1 L Et₂Ounder N₂ atmosphere at rt was added KOt-Bu (5.8 g, 51.6 mmol). Theresulting yellow suspension was stirred until the reaction was judged tobe complete by TLC analysis. 500 mL sat. NaHCO₃ (aq) was added to thereaction mixture, and the organic layer was separated. The aqueous layerwas extracted with Et₂O (500 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 9.7 g ofthe crude epoxide 42 (yellow oil), that was used in the next stepwithout further purification.

To a stirring solution of the crude epoxide 42 (9.7 g) in 115 mL THFunder N₂ atmosphere at −78° C. was added CuI (2.0 g, 10.3 mmol) followedby isopropenyl magnesium bromide (0.50 M in THF, 0.16 L, 77.0 mmol)dropwise. The resulting yellow suspension was stirred for 1 h at −78°C., warmed to rt, and then stirred until the reaction was judged to becomplete by TLC analysis. The reaction was quenched by adding 100 mL ofsat. NH₄Cl (aq) to the reaction mixture. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (500mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo. Purification of the crude product by SiO₂ flashcolumn chromatography using 20% ethyl acetate: 80% hexanes as the eluentafforded 8.8 g of the compound ent-6 as a pale yellow oil (63% over 3steps).

Example 2

Ti-Mediated Coupling Process for Steroid Compound Synthesis (FirstSeries)

2A. Hydrindane 8 and Hydrindane 9

This Example describes the production of intermediates hydrindane 8 andhydrindane 9 used in subsequent reactions.

To a stirring solution of alkyne 7 (1.6 g, 9.0 mmol, 2.7 equiv) in 80 mLof dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (2.6 g,9.0 mmol 2.7 equiv). The resulting mixture was cooled to −78° C., andn-BuLi (2.4 M in hexanes, 7.6 mL, 18.2 mmol, 5.7 equiv) was addeddropwise. The resulting black mixture was warmed first to rt, heated to50° C., and stirred at 50° C. for 1 h (a reflux condenser was not used).In a separate flask under N₂ atmosphere, enyne 6 (0.77 g, 3.4 mmol, 1.0equiv) was dissolved in 10 mL of dry toluene, cooled to −78° C., andtreated with n-BuLi (2.4 M in hexanes, 1.4 mL, 3.4 mmol, 1.0 equiv)dropwise at −78° C. The resulting yellow solution was warmed to rt, andthen transferred by cannula to the black Ti-alkyne complex at −78° C.The mixture was slowly warmed to rt overnight (approx. 17 h). After thisperiod, 80 mL of dry MeOH in a separate flask was cooled to −78° C.under N₂ atmosphere, and the reaction mixture was transferred by cannulato the pre-cooled MeOH. Once the addition was complete, the reactionmixture was warmed to rt, and 100 mL of sat. NaHCO₃ (aq) was added. Thereaction mixture was further diluted with 100 mL Et₂O. The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate(50 mL×3). The combined organic layers were dried over anhydrous MgSO₄,filtered through a coarse fritted glass funnel, and then the solventswere removed in vacuo. Purification of the crude product by flash columnchromatography afforded 0.65 g of the compounds 8 and 9 as a yellow oil(69%, isolated as a 4:1 mixture of 8:9).

The subsequent procedures were used to convert 73 mg of heated thetrans-fused hydrindane 8 to the steroidal product 12 with an overall 28%isolated yield. This yield is based on the amount of hydrindane 8present in a 4:1 mixture with the unreactive “endo” diene isomer 9.

2B. Dibromocyclopropane 10

This Example describes the production of intermediatesdibromocyclopropane 10 used in subsequent reactions.

To a solution of TEBAC (12 mg, 0.052 mmol, 0.22 equiv), and 91 mg of 4:1mixture of hydrindane 8 (73 mg, 0.23 mmol, 1.0 equiv) and itscorresponding endo diene isomer (18 mg, 0.058 mmol) in 2.0 mL CHBr₃ atrt was added KOH (130 mg, 2.3 mmol, 10 equiv) in water (0.1 mL). Theresulting mixture was stirred at 45° C. overnight (approx. 17 h). Thereaction mixture was cooled to rt, then partitioned between 10 mL waterand 20 mL ethyl acetate. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with water, brine, and dried over anhydrousMgSO₄. The resulting suspension was filtered through a coarse frittedglass funnel, and the filtrate was concentrated in vacuo. Purificationof the crude product by flash column chromatography afforded 46 mg ofthe compound dibromocyclopropane 10 as a pale yellow film (41%).

2C. Steroid 12

This Example describes the production of steroid 12 from theintermediate vinylcyclopropane 10. To a solution of compound 10 (46 mg,0.095 mmol, 1.0 equiv) in 1 mL nitromethane was added i-PrOH (57 mg,0.95 mmol, 10 equiv) and TiCl₄ (45 mg, 0.24 mmol, 2.5 equiv). Theresulting mixture was stirred at rt for 1 h under N₂ atmosphere and asecond aliquot of i-PrOH (57 mg, 0.95 mmol, 10 equiv) and TiCl₄ (45 mg,0.24 mmol, 2.5 equiv) was added. The mixture was stirred for another 1 hat rt under N₂ atmosphere, then partitioned between 10 mL sat. NaHCO₃(aq) and 20 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (20 mL×3). The combined organic layerswere washed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 21.3 mg of the title steroidcompound 12 as a yellow amorphous solid (68%).

2D. Hydrindane (ent-8)

This Example describes the production of intermediate hydrindane (ent-8)used in subsequent reactions.

Briefly, to a stirred solution of alkyne 7 (1.1 g, 6.5 mmol, 3.0 equiv)in 40 mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄(1.9 g, 6.5 mmol 3.0 equiv). The resulting mixture was cooled to −78°C., and n-BuLi (2.5 M in hexanes, 5.3 ml, 13 mmol, 6.0 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenser wasnot used). In a separate flask under N₂ atmosphere, enyne ent-6 (0.50 g,2.2 mmol, 1.0 equiv) was dissolved in 13 mL of dry toluene, cooled to−78° C., and then n-BuLi (2.5 M in hexanes, 0.80 mL, 2.0 mmol, 1.0equiv) was added dropwise. The resulting yellow solution was warmed tort, and then transferred by cannula to the black Ti-alkyne complex at−78° C. The mixture was slowly warmed to rt overnight (approx. 17 h).After this period, 50 mL of dry MeOH in a separate flask was cooled to−78° C. under N₂ atmosphere, and the reaction mixture was transferred bycannula to the pre-cooled MeOH. Once the addition was complete, thereaction mixture was warmed to rt, and 30 mL of sat. NaHCO₃ (aq) wasadded. The organic layer was separated using 100 mL Et₂O, and theaqueous layer was extracted with Et₂O (50 mL×2). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered through a coarsefritted glass funnel, and then the filtrate was concentrated in vacuo.Purification of the crude product by flash column chromatographyafforded 0.47 g of the compounds ent-8 and S5 as a yellow oil (69%,isolated as a 4:1 mixture of ent-8:S5).

2E. Steroid (ent-12)

This Example describes the production of steroid ent-12 used insubsequent reactions.

The following two-step procedure was used to convert 88 mg of thetrans-fused hydrindane ent-8 to the steroidal product ent-12 with anoverall 24% isolated yield. This yield is based on the amount ofhydrindane ent-8 present in a 4:1 mixture with the unreactive “endo”diene isomer S5.

To a solution of TEBAC (16 mg, 0.070 mmol, 0.25 equiv), CHBr₃ (0.30 mL,3.4 mmol, 12 equiv), and 0.11 g of a 4:1 mixture of hydrindane ent-8 (88mg, 0.28 mmol, 1.0 equiv) and its corresponding endo diene isomer S5 (22mg, 0.070 mmol) in 2 mL CH₂Cl₂ at rt was added NaOH (0.16 g, 3.9 mmol,14 equiv) in water (0.16 mL). The resulting mixture was stirred at 45°C. overnight (approx. 17 h). The reaction mixture was cooled to rt, thenpartitioned between 10 mL DI water and 20 mL ethyl acetate. The organiclayer was separated and the aqueous layer was extracted with ethylacetate (20 mL×3). The combined organic layers were dried over anhydrousMgSO₄, filtered through a coarse fritted glass funnel and the filtratewas concentrated in vacuo to afford 60 mg of the crude product(tentatively assigned dibromo cyclopropane intermediate).

To a solution of the above crude product (60 mg) in 6 mL nitromethanewas added TiCl₄ (55 mg, 0.29 mmol) dropwise at rt. The resulting mixturewas stirred at rt for 1 h, then partitioned between 30 mL sat. NaHCO₃(aq) and 30 mL CH₂Cl₂. The organic layer was separated and the aqueouslayer was extracted with CH₂Cl₂ (30 mL×3). The combined organic layerswere dried over anhydrous MgSO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 22 mg of compoundent-12 as a yellow amorphous solid (24% over 2 steps).

2F. Hydrindane 14

This Example describes the production of hydrindane 14 used insubsequent reactions.

Briefly, to a stirred solution of alkyne 13 (2.7 g, 13 mmol, 3.0 equiv)in 80 mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄(3.7 g, 13 mmol 3.0 equiv). The resulting mixture was cooled to −78° C.,and n-BuLi (2.3 M in hexanes, 11 ml, 26 mmol, 6.0 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask under N₂ atmosphere, enyne ent-6 (1.0g, 4.3 mmol, 1.0 equiv) was dissolved in 25 mL of dry toluene, cooled to−78° C., and then n-BuLi (2.3 M in hexanes, 1.9 mL, 4.3 mmol, 1.0 equiv)was added dropwise. The resulting yellow solution was warmed to rt, andthen transferred by cannula to the black Ti-alkyne complex at −78° C.The mixture was slowly warmed to rt overnight (approx. 17 h). After thisperiod, 80 mL of dry MeOH in a separate flask was cooled to −78° C.under N₂ atmosphere, and the reaction mixture was transferred by cannulato the pre-cooled MeOH. Once the addition was complete, the reactionmixture was warmed to rt, and 60 mL of sat. NaHCO₃ (aq) was added. Thereaction mixture was further diluted with 200 mL Et₂O. The organic layerwas separated, and the aqueous layer was extracted with Et₂O (100 mL×2).The combined organic layers were dried over anhydrous Na₂SO₄, filteredthrough a coarse fritted glass funnel, and then the filtrate wasconcentrated in vacuo. Purification of the crude product by flash columnchromatography afforded 0.64 g of the compounds hydrindane 14 andintermediate S6 as a yellow oil (43%, isolated as a 5:1 mixture of14:S6).

2G. Steroid 15

This Example describes the production of steroid 15 used in subsequentreactions.

The following three-step procedure was used to convert 0.37 g of thetrans-fused hydrindane 14 to the steroidal product 15 with an overall59% isolated yield. This yield is based on the amount of hydrindane 14present in a 5:1 mixture with the unreactive “endo” diene isomer S6.

To a solution of 0.44 g of a 5:1 mixture of hydrindane 14 (0.37 g, 1.1mmol, 1.0 equiv) and its corresponding endo diene isomer S6 (70 mg, 0.2mmol) in 10 mL THF was added TBSCI (0.94 g, 6.2 mmol, 5.6 equiv) andimidazole (0.52 g, 7.6 mmol, 6.9 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h), thenpartitioned between 10 mL sat. NaHCO₃ (aq) and 10 mL ethyl acetate. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (10 mL×3). The combined organic layers were washed withbrine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo to afford 0.54 g of the crude product (yellowoil), that was used in the next step without further purification.

To a solution of the above crude product (0.54 g) and TEBAC (54 mg, 0.24mmol) in 2.4 mL CHCl₃ at rt was added KOH (0.80 g, 14 mmol) in water(0.8 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between20 mL water and 50 mL CH₂Cl₂. The organic layer was separated, and theaqueous layer was extracted with CH₂Cl₂ (100 mL×3). The combined organiclayers were washed with brine and dried over anhydrous MgSO₄. Theresulting suspension was filtered through a coarse fritted glass funnel,and the filtrate was concentrated in vacuo to afford 0.62 g of the crudeproduct (brown film), that was used in the next step without furtherpurification.

To a solution of the above crude product (0.62 g) in 23 mL nitromethanewas added i-PrOH (1.2 g, 20 mmol) and TiCl₄ (0.31 g, 1.6 mmol). Theresulting mixture was stirred at rt for 1 h under N₂ atmosphere and asecond aliquot of i-PrOH (1.2 g, 20 mmol) and TiCl₄ (0.31 g, 1.6 mmol)was added. The mixture was stirred for another 1 h at rt under N₂atmosphere, then partitioned between 50 mL sat. NaHCO₃ (aq) and 100 mLCH₂Cl₂. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (100 mL×3). The combined organic layers werewashed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 0.20 g of the compound steroid 15as a yellow film (57% over 3 steps).

2H. Hydrindane 17

This Example describes the production of hydrindane 17 used insubsequent reactions.

To a stirring solution of alkyne 16 (0.34 g, 1.3 mmol, 3.0 equiv) in 8mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (0.37g, 1.3 mmol 3.0 equiv). The resulting mixture was cooled to −78° C., andn-BuLi (2.3 M in hexanes, 1.1 ml, 2.6 mmol, 6.0 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask, under N₂ atmosphere, enyne ent-6(0.10 g, 0.43 mmol, 1.0 equiv) was dissolved in 2.5 mL of dry toluene,cooled to −78° C., and then n-BuLi (2.3 M in hexanes, 0.20 mL, 0.46mmol, 1.1 equiv) was added dropwise. The resulting yellow solution waswarmed to rt, and then transferred by cannula to the black Ti-alkynecomplex at −78° C. The mixture was slowly warmed to rt overnight(approx. 17 h). After this period, 8 mL of dry MeOH in a separate flaskwas cooled to −78° C. under N₂ atmosphere, and the reaction mixture wastransferred by cannula to the pre-cooled MeOH. Once the addition wascomplete, the reaction mixture was warmed to rt, and 60 mL of sat.NaHCO₃ (aq) was added. The reaction mixture was further diluted with 20mL Et₂O. The organic layer was separated, and the aqueous layer wasextracted with Et₂O (50 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a coarse fritted glass funnel,and then the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 0.10 g of thehydrindane 17 and intermediate S7 as a yellow film (57%, isolated as2.5:1 mixture of 17:S7).

2I. Steroid 18

This Example describes the production of steroid 18 used in subsequentreactions.

The following three-step procedure was used to convert 0.22 g of thetrans-fused hydrindane 17 to the steroidal product 18 with an overall33% isolated yield. This yield is based on the amount of hydrindane 17present in a 2.5:1 mixture with the unreactive “endo” diene isomer S7.

To a solution of 0.31 g of 2.5:1 mixture of hydrindane 17 (0.22 g, 0.55mmol, 1.0 equiv) and its corresponding endo diene isomer S7 (89 mg, 0.22mmol) in 5 mL THF was added TBSCI (0.58 g, 3.8 mmol, 7.0 equiv) andimidazole (0.31 g, 4.6 mmol, 8.3 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h). The reactionwas partitioned between 10 mL sat. NaHCO₃ (aq) and 20 mL ethyl acetate.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo to afford 0.36 g of the crude product (yellowoil), that was used in the next step without further purification.

To a solution of the above crude product (0.36 g) and TEBAC (35 mg, 0.15mmol) in 1.2 mL CHCl₃ at rt was added KOH (0.50 g, 8.9 mmol) in water(0.50 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between20 mL DI H₂O and 50 mL CH₂Cl₂. The organic layer was separated, and theaqueous layer was extracted with CH₂Cl₂ (100 mL×3). The combined organiclayers were washed with brine and dried over anhydrous MgSO₄. Theresulting suspension was filtered through a coarse fritted glass funnel,and the filtrate was concentrated in vacuo to afford 0.38 g of the crudeproduct (brown oil), that was used in the next step without furtherpurification.

To a solution of the above crude product (0.38 g) in 15 mL nitromethanewas added DI H₂O (0.28 g, 16 mmol) and TiCl₄ (2.1 g, 11 mmol). Theresulting mixture was stirred at rt until the reaction was judged to becomplete by TLC analysis, then partitioned between 50 mL sat. NaHCO₃(aq) and 100 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (100 mL×3). The combined organic layerswere washed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 68 mg of compound steroid 18 as ayellow film (isolated as a single isomer, 33% over 3 steps,regioselectivity could not be determined from the crude ¹H NMRanalysis).

2J. Hydrindane 20

This Example describes the production of hydrindane 20 used insubsequent reactions.

To a stirring solution of alkyne 19 (0.54 g, 2.6 mmol, 3.0 equiv) in 16mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (0.74g, 2.6 mmol 3.0 equiv). The resulting mixture was cooled to −78° C., andn-BuLi (2.4 M in hexanes, 2.2 ml, 5.2 mmol, 6.0 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask, under N₂ atmosphere, enyne ent-6(0.20 g, 0.86 mmol, 1.0 equiv) was dissolved in 5.4 mL of dry toluene,cooled to −78° C., and then n-BuLi (2.4 M in hexanes, 0.37 mL, 0.89mmol, 1.0 equiv) was added dropwise. The resulting yellow solution waswarmed to rt, and then transferred by cannula to the black Ti-alkynecomplex at −78° C. The mixture was slowly warmed to rt overnight(approx. 17 h). After this period, 16 mL of dry MeOH in a separate flaskwas cooled to −78° C. under N₂ atmosphere, and the reaction mixture wastransferred by cannula to the pre-cooled MeOH. Once the addition wascomplete, the reaction mixture was warmed to rt, and 12 mL of sat.NaHCO₃ (aq) was added. The reaction mixture was further diluted with 40mL Et₂O. The organic layer was separated, and the aqueous layer wasextracted with Et₂O (20 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a coarse fritted glass funnel,and the filtrate was concentrated in vacuo. Purification of the crudeproduct by flash column chromatography afforded 0.15 g of the compoundshydrindane 20 and intermediate S8 as a yellow film (51%, isolated as a2.4:1 mixture of 20:S8).

2K. Steroid 21a and Steroid 21b

This Example describes the production of steroid 21a and steroid 21 bused in subsequent reactions.

The following two-step procedure was used to convert 0.15 g of thetrans-fused hydrindane 20 to the steroidal products 21a and 21b.

To a solution of TEBAC (27 mg, 0.12 mmol, 0.27 equiv), CHBr₃ (0.53 mL,6.1 mmol, 14 equiv), and 0.21 g of 2.4:1 mixture of hydrindane 20 (0.15g, 0.43 mmol, 1.0 equiv) and its corresponding endo diene isomer S8 (60mg, 0.17 mmol) in 2.0 mL CH₂Cl₂ at rt was added NaOH (0.49 g, 12 mmol,28 equiv) in water (0.49 mL). The resulting mixture was stirred at rtovernight (approx. 17 h), then partitioned between 10 mL water and 20 mLethyl acetate. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with water, brine, and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 50.0 mg of the product (tentativelyassigned as a dibromo cyclopropane intermediate).

To a solution of the above product in 6 mL nitromethane was added TiCl₄(55 mg, 0.29 mmol, 1.0 equiv) dropwise at rt. The resulting mixture wasstirred at rt for 1 h, then partitioned between 30 mL sat. NaHCO₃ (aq)and 30 mL CH₂Cl₂. The organic layer was separated and aqueous layer wasextracted with CH₂Cl₂ (30 mL×3). The combined organic layers were driedover anhydrous MgSO₄, filtered through a coarse fritted glass funnel,and the filtrate was concentrated in vacuo to afford 25 mg of the crudeproduct (obtained as a 1.6:1 mixture of the two regioisomers 21a and21b).

2L. Hydrindane 23

This Example describes the production of hydrindane 23 used insubsequent reactions.

To a stirring solution of alkyne 22 (2.7 g, 13 mmol, 3.0 equiv) in 89 mLof dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (3.7 g, 13mmol 3.0 equiv). The resulting mixture was cooled to −78° C., and n-BuLi(2.5 M in hexanes, 10.5 ml, 26 mmol, 6.0 equiv) was added dropwise. Theresulting black Ti-alkyne complex was warmed first to rt, then heated to50° C. and stirred at 50° C. for 1 h (a reflux condenser was not used).In a separate flask, under N₂ atmosphere, enyne ent-6 (1.1 g, 4.8 mmol,1.0 equiv) was dissolved in 30 mL of dry toluene, cooled to −78° C., andthen n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol, 1.0 equiv) was addeddropwise. The resulting yellow reaction mixture was warmed to rt, andthen transferred by cannula to the black Ti-alkyne complex at −78° C.The mixture was slowly warmed to rt overnight (approx. 17 h). After thisperiod, 80 mL of dry MeOH in a separate flask was cooled to −78° C.under N₂ atmosphere, and the reaction mixture was transferred by cannulato the pre-cooled MeOH. Once the addition was complete, the reactionmixture was warmed to rt, and 100 mL of DI H₂O was added. The solventswere removed in vacuo, and the remaining aqueous mixture was extractedwith ethyl acetate (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a coarse fritted glass funnel,and then the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 0.94 g of thecompounds hydrindane 23 and S9 as a yellow amorphous solid (55%,isolated as a 5:1 mixture of 23:S9).

2M. Steroid 24

This Example describes the production of steroid 24 used in subsequentreactions.

The following three-step procedure was used to convert 92 mg of thetrans-fused hydrindane 23 to the steroidal product 24 with an overall34% isolated yield. This yield is based on the amount of hydrindane 23present in a 5:1 mixture with the unreactive “endo” diene isomer S9.

To a solution of 0.11 g of 5:1 mixture of hydrindane 23 (92 mg, 0.27mmol, 1.0 equiv) and its corresponding endo diene isomer S9 (18 mg,0.052 mmol) in 3 mL THF was added TBSCI (0.24 g, 1.6 mmol, 5.9 equiv)and imidazole (0.13 g, 1.9 mmol, 7.1 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h). The reactionwas partitioned between 10 mL sat. NaHCO₃ (aq) and 50 mL ethyl acetate.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (50 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo to afford 0.17 g of the crude product (yellowoil), which was used in the next step without further purification.

To a solution of the above crude product (0.17 g) and TEBAC (35 mg, 0.15mmol) in 0.6 mL CHBr₃ at rt was added KOH (0.25 g, 4.5 mmol) in water(0.25 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between20 mL water and 50 mL CH₂Cl₂. The organic layer was separated, and theaqueous layer was extracted with CH₂Cl₂ (100 mL×3). The combined organiclayers were washed with brine and dried over anhydrous MgSO₄. Theresulting suspension was filtered through a coarse fritted glass funnel,and the filtrate was concentrated in vacuo to afford 0.21 g of the crudeproduc (brown oil), which was used in the next step without furtherpurification.

To a solution of the above crude product (0.21 g) in 6 mL nitromethanewas added i-PrOH (0.18 g, 30.0 mmol) and TiCl₄ (0.14 g, 0.75 mmol). Theresulting mixture was stirred until the reaction was judged to becomplete by TLC analysis, then partitioned between 50 mL sat. NaHCO₃(aq) and 50 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (50 mL×3). The combined organic layerswere washed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 33 mg of the compound steroid 24 asa brown film (34% over 3 steps).

2N. Alkyne 25

This Example describes the production of alkyne 25 used in subsequentreactions.

To a stirring solution of aryl iodide S10 (10.0 g, 33 mmol, 1.0 equiv),PdCl₂(PPh₃)₂ (0.46 g, 0.66 mmol, 2 mol %), and CuI (0.25 g, 1.3 mmol, 4mol %) in 82 mL triethylamine under N₂ atmosphere at rt was addedTMS-acetylene (3.89 g, 40.0 mmol, 1.2 equiv) dropwise. The resultingyellow suspension was stirred overnight under N₂ atmosphere at rt(approx. 17 h). The reaction mixture was filtered through a pad ofcelite, and the filtrate was concentrated in vacuo. The crude oil wasdissolved in hexanes, and then passed through a pad of silica using 95%hexanes: 5% ethyl acetate as the eluent. The resulting solution wasdried over anhydrous Na₂SO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 8.7 g ofthe compound alkyne 25 as a yellow amorphous solid (96%).

2O. Hydrindane 26

This Example describes the production of hydrindane 26 used insubsequent reactions.

To a stirring solution of alkyne 25 (3.6 g, 13 mmol, 3.0 equiv) in 80 mLof dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (3.7 g, 13mmol 3.0 equiv). The resulting mixture was cooled to −78° C., and n-BuLi(2.3 M in hexanes, 11 ml, 26 mmol, 6.0 equiv) was added dropwise. Theresulting black Ti-alkyne complex was warmed first to rt, then heated to50° C. and stirred at 50° C. for 1 h (a reflux condenser was not used).In a separate flask, under N₂ atmosphere, enyne ent-6 (1.0 g, 4.3 mmol,1.0 equiv) was dissolved in 20 mL of dry toluene, cooled to −78° C., andthen n-BuLi (2.3 M in hexanes, 1.9 mL, 4.3 mmol, 1.0 equiv) was addeddropwise. The resulting yellow solution was warmed to rt, and thentransferred by cannula to the black Ti-alkyne complex at −78° C. Themixture was slowly warmed to rt overnight (approx. 17 h). After thisperiod, 80 mL of dry MeOH in a separate flask was cooled to −78° C.under N₂ atmosphere, and the reaction mixture was transferred by cannulato the pre-cooled MeOH. Once the addition was complete, the reactionmixture was warmed to rt, and 70 mL of sat. NaHCO₃ (aq) was added. Thereaction mixture was further diluted with 100 mL Et₂O. The organic layerwas separated, and the aqueous layer was extracted with Et₂O (100 mL×2).The combined organic layers were dried over anhydrous Na₂SO₄, filteredthrough a coarse fritted glass funnel, and the filtrate was concentratedin vacuo. Purification of the crude product by flash columnchromatography afforded 0.87 g of compound hydrindane 26 and S11 as ayellow oil (49%, isolated as a 2.3:1 mixture of 26:S11).

2P. Steroid 27

This Example describes the production of steroid 27 used in subsequentreactions.

The following three-step procedure was used to convert 0.16 g of thetrans-fused hydrindane 26 to the steroidal product 27 with an overall31% isolated yield. This yield is based on the amount of hydrindane 26present in a 2.3:1 mixture with the unreactive “endo” diene isomer S11.

To a solution of 0.23 g of 2.3:1 mixture of hydrindane 26 (0.16 g, 0.39mmol, 1.0 equiv) and its corresponding endo diene isomer S11 (70.0 mg,0.17 mmol) in 5 mL THF was added TBSCI (0.42 g, 2.8 mmol, 7.2 equiv) andimidazole (0.23 g, 3.4 mmol, 8.7 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h). The reactionwas partitioned between 10 mL sat. NaHCO₃ (aq) and 20 mL ethyl acetate.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo to afford 0.25 g of the crude product (yellow oil)that was used in the next step without further purification.

To a solution of the above crude product (0.25 g) and TEBAC (25 mg, 0.11mmol) in 1.0 mL CHCl₃ at rt was added KOH (0.38 g, 6.8 mmol) in water(0.38 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between20 mL DI water and 50 mL CH₂Cl₂. The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (100 mL×3). The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄.The resulting suspension was filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 0.28 g ofthe crude product (brown film) that was used in the next step withoutfurther purification.

To a solution of the above crude product (0.28 g) in 11 mL nitromethanewas added DI H₂O (0.20 g, 11 mmol) and TiCl₄ (2.1 g, 11 mmol). Theresulting mixture was stirred at rt until the reaction was judged to becomplete by TLC analysis, then partitioned between 50 mL sat. NaHCO₃(aq) and 100 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (100 mL×3). The combined organic layerswere washed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 46 mg of the compound steroid 27 asa yellow film (isolated as a single regioisomer. 31% over 3 steps,regioselectivity could not be determined from the crude ¹H NMRanalysis).

2Q. Alkyne 28

This Example describes the production of alkyne 28 used in subsequentreactions.

To a stirring solution of aryl iodide S12 (5.0 g, 20 mmol, 1.0 equiv),PdCl₂(PPh₃)₂ (0.28 g, 0.40 mmol, 2 mol %), and CuI (0.15 g, 0.79 mmol, 4mol %) in 50 mL triethylamine under N₂ atmosphere at rt was addedTMS-acetylene (2.4 g, 24 mmol, 1.2 equiv) dropwise. The resulting yellowsuspension was stirred overnight (approx. 17 h) under N₂ atmosphere atrt. The reaction mixture was filtered through a pad of celite, and thefiltrate was concentrated in vacuo. The crude oil was dissolved inhexanes, and then passed through a pad of silica using 95% hexanes: 5%ethylacetate as the eluent. The resulting solution was dried overanhydrous Na₂SO₄, filtered through a coarse fritted glass funnel, andthe filtrate was concentrated in vacuo to afford 4.1 g of compoundalkyne 28 as a yellow solid (93%).

2R. Hydrindane 29

This Example describes the production of hydrindane 29 used insubsequent reactions.

To a stirring solution of alkyne 28 (1.1 g, 5.0 mmol, 3.1 equiv) in 30mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (1.3 g,4.7 mmol 2.9 equiv). The resulting mixture was cooled to −78° C., andn-BuLi (2.4 M in hexanes, 4.1 mL, 9.7 mmol, 6.0 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask, under N₂ atmosphere, enyne ent-6(0.37 g, 1.6 mmol, 1.0 equiv) was dissolved in 10 mL of dry toluene,cooled to −78° C., and then n-BuLi (2.4 M in hexanes, 0.68 mL, 1.6 mmol,1.0 equiv) was added dropwise. The resulting yellow reaction mixture waswarmed to rt, and then transferred by cannula to the black Ti-alkynecomplex at −78° C. The mixture was slowly warmed to rt overnight(approx. 17 h). After this period, 30 mL of dry MeOH in a separate flaskwas cooled to −78° C. under N₂ atmosphere, and the reaction mixture wastransferred by cannula to the pre-cooled MeOH. Once the addition wascomplete, the reaction mixture was warmed to rt, and 30 mL of sat.NaHCO₃ (aq) was added. The reaction mixture was further diluted with 50mL Et₂O. The organic layer was separated, and the aqueous layer wasextracted with Et₂O (100 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a coarse fritted glass funnel,and then the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 0.87 g of thecompound hydrindane 29 and S13 as a yellow oil (52%, isolated as a 4:1mixture of 29:S13).

2S. Steroid 30

This Example describes the production of steroid 30 used in subsequentreactions.

The following three-step procedure was used to convert 0.10 g of thetrans-fused hydrindane 29 to the steroidal product 30 with an overall68% isolated yield. This yield is based on the amount of hydrindane 29present in a 4:1 mixture with the unreactive “endo” diene isomer S13.

To a solution of 0.13 g of 4:1 mixture of hydrindane 29 (0.10 g, 0.28mmol, 1.0 equiv) and its corresponding endo diene isomer S13 (26.0 mg,0.073 mmol) in 5 mL THF was added TBSCI (0.27 g, 1.8 mmol, 6.4 equiv)and imidazole (0.14 g, 2.1 mmol, 7.3 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h), thenpartitioned between 50 mL sat. NaHCO₃ (aq) and 50 mL hexanes. Theorganic layer was separated, and the aqueous layer was extracted withhexanes (20 mL×3). The combined organic layers were dried over anhydrousMgSO₄, filtered through a coarse fritted glass funnel, and the filtratewas concentrated in vacuo to afford 0.16 g of the crude product (yellowoil), that was used in the next step without further purification.

To a solution of the above crude product (0.16 g) and TEBAC (16 mg,0.070 mmol) in 0.7 mL CHCl₃ at rt was added KOH (0.24 g, 4.3 mmol) inwater (0.24 mL). The reaction mixture was stirred at 45° C. overnight(approx. 17 h). The reaction mixture was cooled to rt, then partitionedbetween 10 mL DI water and 50 mL CH₂Cl₂. The organic layer wasseparated, and the aqueous layer was extracted with CH₂Cl₂ (50 mL×2).The combined organic layers were dried over anhydrous MgSO₄, filteredthrough a coarse fritted glass funnel, and the filtrate was concentratedin vacuo to afford 0.18 g of the crude product (brown film), that wasused in the next step without further purification.

To a solution of the above crude product (0.18 g) in 7 mL nitromethanewas added i-PrOH (0.20 g, 3.3 mmol) and TiCl₄ (0.16 g, 0.84 mmol). Theresulting mixture was stirred at rt until the reaction was judged to becomplete by TLC analysis, then partitioned between 10 mL sat. NaHCO₃(aq) and 50 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (50 mL×2). The combined organic layerswere dried over anhydrous MgSO₄, filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 66 mg of thecompound steroid 30 as a yellow film (68% over 3 steps).

2T. Hydrindane 32

This Example describes the production of hydrindane 32 used insubsequent reactions.

To a stirring solution of alkyne 31 (2.4 g, 13 mmol, 3.0 equiv) in 80 mLof dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (3.7 g, 13mmol 3.0 equiv). The resulting mixture was cooled to −78° C., and n-BuLi(2.4 M in hexanes, 11 mL, 26 mmol, 6.0 equiv) was added dropwise. Theresulting black Ti-alkyne complex was warmed first to rt, then heated to50° C. and stirred at 50° C. for 1 h (a reflux condenser was not used).In a separate flask, under N₂ atmosphere, enyne ent-6 (1.0 g, 4.3 mmol,1.0 equiv) was dissolved in 20 mL of dry toluene, cooled to −78° C., andthen n-BuLi (2.4 M in hexanes, 1.8 mL, 4.3 mmol, 1.0 equiv) was addeddropwise. The resulting yellow solution was warmed to rt, and thentransferred by cannula to the black Ti-alkyne complex at −78° C. Themixture was slowly warmed to rt overnight (approx. 17 h). After thisperiod, 80 mL of dry MeOH in a separate flask was cooled to −78° C.under N₂ atmosphere, and the reaction mixture was transferred by cannulato the pre-cooled MeOH. Once the addition was complete, the reactionmixture was warmed to rt, and 70 mL of sat. NaHCO₃ (aq) was added. Thereaction mixture was further diluted with 100 mL Et₂O. The organic layerwas separated, and the aqueous layer was extracted with Et₂O (100 mL×2).The combined organic layers were dried over anhydrous Na₂SO₄, filteredthrough a coarse fritted glass funnel, and then the filtrate wasconcentrated in vacuo. Purification of the crude product by flash columnchromatography afforded 0.69 g of compounds hydrindane 32 and S14 as ayellow oil (49%, isolated as a 5:1 mixture of 32:S14).

2U. Steroid 33

This Example describes the production of steroid 33 used in subsequentreactions.

The following three-step procedure was used to convert 0.31 g of thetrans-fused hydrindane 32 to the steroidal product 33 and intermediateS15 with an overall 47% combined yield. This yield is based on theamount of hydrindane 32 present in a 3:1 mixture with the unreactive“endo” diene isomer S14.

To a solution of 0.37 g of 5:1 mixture of hydrindane 32 (0.31 g, 0.97mmol, 1.0 equiv) and its corresponding endo diene isomer (60.0 mg, 0.19mmol) in 10 mL THF was added TBSCI (0.83 g, 5.5 mmol, 5.7 equiv) andimidazole (0.47 g, 6.9 mmol, 7.1 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h), thenpartitioned between 10 mL sat. NaHCO₃ (aq) and 20 mL ethyl acetate. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (20 mL×3). The combined organic layers were dried overanhydrous MgSO₄, filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo to afford 0.43 g of the crude product(yellow oil), that was used in the next step without furtherpurification.

To a solution of the above crude product (0.43 g) and TEBAC (45 mg, 0.20mmol) in 2.0 mL CHCl₃ at rt was added KOH (0.67 g, 12 mmol) in water(0.67 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between10 mL DI water and 50 mL CH₂Cl₂. The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (100 mL×3). The combinedorganic layers were dried over anhydrous MgSO₄, filtered through acoarse fritted glass funnel, and the filtrate was concentrated in vacuoto afford 0.54 g of the crude product (brown film), that was used in thenext step without further purification.

To a solution of the above crude product (0.54 g) in 20 mL nitromethanewas added i-PrOH (0.79 g, 13 mmol) and TiCl₄ (0.50 g, 2.6 mmol). Theresulting mixture was stirred at rt for h under N₂ atmosphere and asecond aliquot of i-PrOH (0.79 g, 13 mmol) and TiCl₄ (0.50 g, 2.6 mmol)was added. The mixture was stirred for another 1 h at rt under N₂atmosphere, then partitioned between 50 mL sat. NaHCO₃ (aq) and 100 mLCH₂Cl₂. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (100 mL×3). The combined organic layers werewashed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 0.13 g of compounds steroid 33 andintermediate S15 as a yellow amorphous solid (46% as a 3:1 mixture of 33and S15 over 3 steps). The analytical samples for 33 and S15 wereobtained by HPLC purification using a small amount (<50 mg) of themixture.

2V. Hydrindane S16

This Example describes the production of hydrindane S16 used insubsequent reactions.

Briefly, to a stirred solution of alkyne 7 (0.71 g, 4.1 mmol, 2.7 equiv)in 40 mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄(1.2 g, 4.1 mmol 2.7 equiv). The resulting mixture was cooled to −78°C., and n-BuLi (2.4 M in hexanes, 3.6 mL, 8.6 mmol, 5.7 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask, under N₂ atmosphere, enyne S3 (368mg, 1.5 mmol, 1.0 equiv) was dissolved in 5 mL of dry toluene, cooled to−78° C., and then n-BuLi (2.4 M in hexanes, 0.63 mL, 1.5 mmol, 1.0equiv) was added dropwise. The resulting yellow solution was warmed tort, and then transferred by cannula to the black Ti-alkyne complex at−78° C. The mixture was slowly warmed to rt overnight (approx. 17 h).After this period, 40 mL of dry MeOH in a separate flask was cooled to−78° C. under N₂ atmosphere, and the reaction mixture was transferred bycannula to the pre-cooled MeOH. Once the addition was complete, thereaction mixture was warmed to rt, and 30 mL of sat. NaHCO₃ (aq) wasadded. The reaction mixture was further diluted with 100 mL Et₂O. Theorganic layer was separated, and the aqueous layer was extracted withEt₂O (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered through a coarse fritted glass funnel, and then thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 221 mg of compounds hydrindane S16and S17 as a yellow oil (45%, isolated as a 1.4:1 mixture of S16:S17).

2W. Steroid 34

This Example describes the production of steroid 34 used in subsequentreactions.

The following three-step procedure was used to convert 112 mg of thetrans-fused hydrindane S16 to the steroidal product 34 with an overall38% isolated yield. This yield is based on the amount of hydrindane S16present in a 1.4:1 mixture with the unreactive “endo” diene isomer S17.

To a solution of 0.19 g of 1.4:1 mixture of hydrindane S16 (0.11 g, 0.34mmol, 1.0 equiv) and its corresponding endo diene isomer S17 (80.0 mg,0.24 mmol) in 10 mL THF was added TBSCI (0.11 g, 0.71 mmol, 2.0 equiv)and imidazole (60.0 mg, 0.88 mmol, 2.6 equiv). The reaction mixture wasstirred at rt under N₂ atmosphere overnight (approx. 17 h). The reactionwas partitioned between 20 mL sat. NaHCO₃ (aq) and 20 mL ethyl acetate.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo. The crude product was passed through a pad ofsilica gel using 99% hexanes: 1% ethyl acetate as the eluent, and thefiltrate was concentrated in vacuo to afford 0.20 g of the crude product(yellow oil), that was used in the next step without furtherpurification.

To a solution of 86% weight of the above crude product (0.17 g) andTEBAC (18 mg, 0.080 mmol) in 2 mL CHCl₃ at rt was added KOH (0.35 g, 6.3mmol) in water (0.35 mL). The reaction mixture was stirred at 45° C.overnight (approx. 17 h). The reaction mixture was cooled to rt, thenpartitioned between 10 mL DI water and 20 mL CH₂Cl₂. The organic layerwas separated, and the aqueous layer was extracted with CH₂Cl₂ (20mL×3). The combined organic layers were washed with brine and dried overanhydrous MgSO₄. The resulting suspension was filtered through a coarsefritted glass funnel, and the filtrate was concentrated in vacuo toafford 0.21 g of the crude product (brown film), that was used in thenext step without further purification.

To a solution of the above crude product (0.21 g) in 2 mL nitromethanewas added i-PrOH (0.25 g, 4.1 mmol) and TiCl₄ (0.19 g, 1.0 mmol). Theresulting mixture was stirred at rt for 1 h under N₂ atmosphere and asecond aliquot of i-PrOH (0.25 g, 4.1 mmol) and TiCl₄ (0.19 g, 1.0 mmol)was added. The mixture was stirred for another 1 h at rt under N₂atmosphere, then partitioned between 20 mL sat. NaHCO₃ (aq) and 50 mLCH₂Cl₂. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (50 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo. Purification of the crude product by flash columnchromatography afforded 34 mg of the compound steroid 34 as a yellowfilm (38% over 3 steps).

2X. Hydrindane S18

This Example describes the production of hydrindane S18 used insubsequent reactions.

Briefly, to a stirred solution of alkyne 7 (1.5 g, 8.8 mmol, 2.7 equiv)in 80 mL of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄(2.5 g, 8.8 mmol 2.7 equiv). The resulting mixture was cooled to −78°C., and n-BuLi (2.4 M in hexanes, 7.9 mL, 18.6 mmol, 5.7 equiv) wasadded dropwise. The resulting black Ti-alkyne complex was warmed firstto rt, then heated to 50° C. and stirred at 50° C. for 1 h (a refluxcondenser was not used). In a separate flask, under N₂ atmosphere, enyneS4 (1.0 g, 3.3 mmol, 1.0 equiv) was dissolved in 10 mL of dry toluene,cooled to −78° C., and then n-BuLi (2.4 M in hexanes, 1.4 mL, 3.3 mmol,1.0 equiv) was added dropwise. The resulting yellow solution was warmedto rt, and then transferred by cannula to the black Ti-alkyne complex at−78° C. The mixture was slowly warmed to rt overnight (approx. 17 h).After this period, 80 mL of dry MeOH in a separate flask was cooled to−78° C. under N₂ atmosphere, and the reaction mixture was transferred bycannula to the pre-cooled MeOH. Once the addition was complete, thereaction mixture was warmed to rt, and 50 mL of sat. NaHCO₃ (aq) wasadded. The reaction mixture was further diluted with 100 mL Et₂O. Theorganic layer was separated, and the aqueous layer was extracted withEt₂O (50 mL×2). The combined organic layers were dried over anhydrousNa₂SO₄, filtered through a coarse fritted glass funnel, and then thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 442 mg of compound hydrindane S18(35%) as a yellow oil and 393 mg of hydrindane S19 (31%) as a yellowoil.

2Y. Steroid 35

This Example describes the production of steroid 35 used in subsequentreactions.

To a solution of hydrindane S18 (0.37 g, 0.95 mmol, 1.0 equiv) in 20 mLTHF was added TBSCI (0.17 g, 1.1 mmol, 1.2 equiv) and imidazole (97 mg,1.4 mmol, 1.5 equiv). The reaction mixture was stirred at rt under N₂atmosphere overnight (approx. 17 h), then partitioned between 20 mL sat.NaHCO₃ (aq) and 20 mL ethyl acetate. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine and dried over anhydrousMgSO₄. The resulting suspension was filtered through a coarse frittedglass funnel, and the filtrate was concentrated in vacuo. The crudeproduct was passed through a pad of silica gel using 99% hexanes:1%ethyl acetate as the eluent, and the filtrate was concentrated in vacuoto afford 465 mg of the crude product (yellow oil), that was used in thenext step without further purification.

To a solution of 86% weight of the above crude product (465 mg) andTEBAC (41 mg, 0.18 mmol) in 1.8 mL CHCl₃ at rt was added KOH (0.73 g, 13mmol) in water (0.7 mL). The reaction mixture was stirred at 45° C.overnight (approx. 17 h). The reaction mixture was cooled to rt, thenpartitioned between 10 mL DI water and 20 mL CH₂Cl₂. The organic layerwas separated, and the aqueous layer was extracted with CH₂Cl₂ (20mL×3). The combined organic layers were washed with brine and dried overanhydrous MgSO₄. The resulting suspension was filtered through a coarsefritted glass funnel, and the filtrate was concentrated in vacuo toafford 348 mg of the crude product (brown oil), that was used in thenext step without further purification.

To a solution of 50% weight of the above crude product (170 mg) in 2 mLnitromethane was added i-PrOH (0.20 g, 3.4 mmol) and TiCl₄ (0.16 g, 0.85mmol). The resulting mixture was stirred at rt for 1 h under N₂atmosphere, and a second aliquot of i-PrOH (0.20 g, 3.4 mmol) and TiCl₄(0.16 g, 0.85 mmol) was added. The mixture was stirred for another 1 hat rt under N₂ atmosphere, then partitioned between 20 mL sat. NaHCO₃(aq) and 30 mL CH₂Cl₂. The organic layer was separated, and the aqueouslayer was extracted with CH₂Cl₂ (20 mL×3). The combined organic layerswere washed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography afforded 55 mg of compound steroid 35 as ayellow film (32% over 3 steps).

2Z. Steroid 36

This Example describes the production of steroid 36 used in subsequentreactions.

To a solution of hydrindane S20 (31 mg, 0.10 mmol, 1.0 equiv) in 3 mLTHF was added TBSCI (18 mg, 0.12 mmol, 1.2 equiv) and imidazole (10.0mg, 0.15 mmol, 1.5 equiv). The reaction mixture was stirred at rt underN₂ atmosphere overnight (approx. 17 h), then partitioned between 3 mLsat. NaHCO₃ (aq) and 5 mL ethyl acetate. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (10mL×3). The combined organic layers were washed with brine, dried overanhydrous MgSO₄, and filtered through a course fritted glass funnel. Thefiltrate was concentrated in vacuo, and the crude product was passedthrough a pad of silica gel using 98% hexanes: 2% ethyl acetate as theeluent. The filtrate was concentrated in vacuo to afford 50 mg of thecrude product (yellow oil), that was used in the next step withoutfurther purification.

To a solution of the above crude product (50 mg) and TEBAC (4.5 mg,0.020 mmol) in 1.8 mL CHCl₃ at rt was added KOH (89 mg, 1.6 mmol) inwater (0.1 mL). The reaction mixture was stirred at 45° C. overnight(approx. 17 h). The reaction mixture was cooled to rt, then partitionedbetween 5 mL water and 10 mL CH₂Cl₂. The organic layer was separated,and the aqueous layer was extracted with CH₂Cl₂ (10 mL×3). The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄.The resulting suspension was filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 55 mg ofthe crude product (brown film), that was used in the next step withoutfurther purification.

To a solution of the above crude product (55 mg) in 2 mL nitromethanewas added i-PrOH (60.0 mg, 1.0 mmol) and TiCl₄ (47 mg, 0.25 mmol). Theresulting mixture was stirred at rt for 1 h under N₂ atmosphere, and asecond aliquot of i-PrOH (60.0 mg, 1.0 mmol) and TiCl₄ (47 mg, 0.25mmol) was added. The mixture was stirred for another 1 h at rt under N₂atmosphere, then partitioned between 10 mL sat. NaHCO₃ (aq) and 15 mLCH₂Cl₂. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (15 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo. Purification of the crude product by flash columnchromatography afforded 11.4 mg of compound steroid 36 as a yellow film(40% over 3 steps).

Example 3

Steroid Compound Synthesis (Second Series)

3A. Steroid 201a

This Example describes the production of steroid 201a used in subsequentreactions.

Synthesis of Steroid 201a:

This compound was prepared by following a procedure described herein. Toa flask containing alkyne 203 (48 g, 234.47 mmol) in anhydrous toluene(1.6 L) under nitrogen atmosphere was added Ti(Oi-Pr)₄ (70 mL, 234.47mmol). The flask was cooled to −78° C. and n-BuLi (2.6 M in hexanes, 200mL, 494.99 mmol) was cannulated drop-wise into the flask. After theaddition of n-BuLi, the flask was warmed to room temperature. Once itreaches room temperature, it was heated to 50° C. for an hour, and thencooled to room temperature. A separate flask containing a solution ofenyne 202 (20 g, 86.84 mmol) in anhydrous toluene (250 mL) was prepared.This flask was cooled to −78° C., and then n-BuLi (2.6 M in hexanes, 35mL, 86.84 mmol) was added and warmed to room temperature. This enynemixture was then transferred into the first reaction flask at −78° C.The combined reaction mixture was stirred at room temperature forovernight (approximately 24 h). The next morning, the reaction mixturewas transferred drop-wise into a flask containing anhydrous MeOH (1.6 L)at −78° C. under nitrogen. The resulting mixture was concentrated invacuo to remove MeOH. After concentration, the mixture was carefullyquenched with saturated aqueous NaHCO₃. The aqueous layer was separatedfrom the organic layer and extracted with ethyl acetate (×3). Thecombined organic layers were dried over anhydrous MgSO₄, and theresulting mixture was vacuum filtered through a coarse fritted glassfunnel. The filtrate was concentrated in vacuo to afford hydrindane 204(14.21 g).

To a solution of hydrindane 204 (14.21 g, 41.48 mmol) in anhydrous THF(600 mL) were added TBSCI (13 g, 91.08 mmol), imidazole (6 g, 91.08mmol) and DMAP (0.3 g, 2.33 mmol). The reaction mixture was stirred atroom temperature under nitrogen atmosphere overnight (approximately 15h) and quenched with saturated aqueous NaHCO₃. The aqueous layer wasseparated from the organic layer and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous MgSO₄, and theresulting mixture was vacuum filtered through a coarse fritted glassfunnel. The filtrate was concentrated in vacuo to afford the crudeproduct (16 g), which was used in the next step without furtherpurification.

To a solution of the above product (16 g, 35.02 mmol) in CH₃Br (75 mL)were added TEBAC (2 g, 8.78 mmol) and a premixed solution of KOH (20 g,356 mmol) in DI water (20 mL). The reaction mixture was stirred at 45°C. overnight (approximately 16 h) and quenched with DI water. Theaqueous layer was separated from the organic layer and extracted withethyl acetate (×3). The combined organic layers were washed with brineand dried over anhydrous MgSO₄. The resulting mixture was vacuumfiltered through a coarse fritted glass funnel. The filtrate wasconcentrated in vacuo to afford the crude product (20 g), which was usedin the next step without further purification.

To a solution of the crude product from the previous step (20 g, 31mmol) in MeNO₂ (620 mL) was added TiCl₄ (8.5 mL, 77.5 mmol) and i-PrOH(23.5 mL, 310 mmol). After the reaction mixture was stirred at roomtemperature for an hour, a second portion of TiCl₄ (8.5 mL, 77.5 mmol)and i-PrOH (23.5 mL, 310 mmol) was added. The reaction mixture wasstirred at room temperature for an hour and quenched with saturatedaqueous NaHCO₃. The aqueous layer was separated from the organic layerand extracted with DCM (×3). The combined organic layers were dried overanhydrous MgSO₄, and the resulting mixture was vacuum filtered through acoarse fritted glass funnel. The filtrate was concentrated in vacuo toafford the crude product, which was purified by flash columnchromatography on silica gel with 90:10 to 70:30 hexanes-ethyl acetategradient elution to afford steroid 201a (5.76 g, 18% over 4 steps) as ayellow solid.

Analytical Data for 201a:

TLC (SiO₂) R_(f)=0.26 (hexanes:ethylacetate-60:40); [α]₅₈₉ ^(T)=+33.915(c 0.0055, CHCl₃); ¹H NMR (600 NMR, CDCl₃) δ 8.12 (d, J=9.1 Hz, 1H),7.34 (s, 1H), 7.24-7.08 (m, 2H), 4.69 (m, 1H), 3.93 (s, 3H), 3.24-3.11(m, 2H), 3.07 (m, 1H), 2.30 (dd, J=12.5, 7.3 Hz, 1H), 2.24-2.15 (m, 2H),2.15-2.07 (m, 1H), 1.89 (td, J=11.8, 7.8 Hz, 1H), 1.74 (br s, 1H), 1.42(dd, J=12.5, 5.7 Hz, 1H), 0.65 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ158.14, 137.95, 134.52, 129.43, 129.41, 126.57, 125.75, 120.46, 118.06,102.27, 72.12, 55.35, 50.55, 47.77, 41.41, 37.22, 35.83, 24.65, 17.75;IR (thin film, cm⁻¹) 3360, 2998, 2937, 2854, 2831, 1713, 1623, 1590,1509, 1448, 1430, 1416, 1376, 1359, 1347, 1315, 1158, 1118, 1088, 1060;HRMS (ESI-TOF) m/z: [M+H] Calculated for C₁₉H₂₂O₂Br 361.0803; Found361.0786.

3B. Steroid 201b

This Example describes the production of steroid 201b.

Synthesis of Steroid 201b:

To a stirring mixture of steroid 201a (30 mg, 0.083 mmol) in 0.6 mL MeOHand 0.15 mL DCM under nitrogen atmosphere was added 10% Pd/C (8.8 mg,0.0083 mmol) at room temperature. A balloon was used to introduce anatmosphere of hydrogen gas into the flask (allowing first for exchangeof the nitrogen atmosphere), and the reaction was stirred under aslightly positive pressure of hydrogen for approximately 8 h. Themixture was filtered through a cotton pipet and rinsed with DCM. Theresulting solution was concentrated in vacuo to afford the crudeproduct, which was purified by flash column chromatography on silica gelwith 60:40 hexanes-ethyl acetate to afford steroid 201 b (19 mg, 81%) asa white solid.

Analytical Data for 201 b:

TLC (SiO₂) R_(f)=0.16 (hexanes:ethyl acetate-75:25); [α]₅₈₉ ^(T)=+40.652(c 0.0089, CHCl₃); ¹H NMR (600 NMR, CDCl₃) δ 7.72 (d, J=8.9 Hz, 1H),7.60 (d, J=8.3 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.15-7.05 (m, 2H),4.76-4.65 (m, 1H), 3.94 (s, 3H), 3.28-3.19 (m, 2H), 3.19-3.10 (m, 1H),2.32 (dd, J=12.4, 7.3 Hz, 1H), 2.27-2.17 (m, 2H), 2.18-2.09 (m, 1H),1.93 (td, J=11.8, 7.8 Hz, 1H), 1.48-1.39 (m, 1H), 0.67 (s, 3H); ¹³C NMR(150 MHz, CDCl₃) δ 157.69, 136.85, 133.03, 130.12, 129.27, 127.45,125.79, 122.70, 116.93, 101.90, 72.32, 55.26, 50.75, 48.01, 41.47,37.33, 36.04, 24.63, 17.76; IR (thin film, cm⁻¹) 3343, 2998, 2937, 2858,1623, 1596, 1518, 1512, 1456; HRMS (ESI-TOF) m/z: [M+H] Calculated forC₁₉H₂₃O₂ 283.1698; Found 283.1688.

3C. Steroid 201c

This Example describes the production of steroid 201c.

Synthesis of Steroid 201c:

To a Schlenk tube containing 201a (20 mg, 0.0553 mmol), Pd(PPh₃)₂Cl₂(1.94 mg, 0.0027 mmol) and CuI (1.05 mg, 0.00553 mmol) under nitrogenatmosphere at room temperature was added anhydrous triethylamine (15 μL,0.1107 mmol) and anhydrous DMF (2 mL) followed by phenylacetylene (12μL, 0.1107 mmol). The reaction mixture was stirred at 80° C. overnight(approximately 15 h). The resulting mixture was concentrated in vacuo,and DMF was removed by dissolving the mixture in diethyl ether andextracting with water. The organic layer was then concentrated in vacuoto afford the crude product, which was purified by flash columnchromatography on silica gel with 60:40 hexanes-ethyl acetate to affordsteroid 201c (19 mg, 89%) as a light yellow solid.

Analytical Data for 201c:

TLC (SiO₂) R_(f)=0.26 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+30.332(c 0.385, CHCl₃); ¹H NMR (600 NMR, CDCl₃) δ 8.35 (d, J=9.1 Hz, 1H), 7.64(d, J=6.8 Hz, 2H), 7.37 (m, 4H), 7.21 (d, J=8.4 Hz, 2H), 4.72 (p, J=5.8Hz, 1H), 3.95 (s, 3H), 3.20 (m, 3H), 2.32 (dd, J=12.4, 7.3 Hz, 1H),2.28-2.20 (m, 2H), 2.15 (dd, J=12.5, 7.6 Hz, 1H), 1.94 (td, J=11.6, 8.3Hz, 1H), 1.60 (s, 1H), 1.45 (dd, J=12.4, 5.7 Hz, 1H), 0.67 (s, 3H); ¹³CNMR (150 MHz, CDCl₃) δ 158.02, 136.67, 133.08, 131.61, 130.92, 128.48,128.40, 128.20, 127.22, 127.16, 123.58, 118.51, 117.61, 102.29, 93.44,88.15, 72.26, 55.30, 50.64, 47.80, 41.42, 37.31, 35.93, 24.85, 17.77; IR(thin film, cm⁻¹) 3423, 2955, 2924, 2857, 1556, 1540, 1519, 1506, 1487,1336, 1267, 1227, 1059, 1047, 1029; HRMS (ESI-TOF) m/z: [M+H] Calculatedfor C₂₇H₂₇O₂ 383.2011; Found 383.1995.

3D. Steroid 205a

This Example describes the production of steroid 205a used in subsequentreactions.

Synthesis of Steroid 205a:

To a solution of 201a (400 mg, 1.107 mmol) in anhydrous toluene (11 mL)at room temperature was added DIBALH (1.0 M in toluene, 11.07 mL, 11.07mmol). The reaction mixture was refluxed at 100° C. overnight(approximately 15 h). After the resulting solution was cooled to roomtemperature, it was quenched by the careful addition of Rochelle's saltand stirred for about 30 mins. The aqueous layer was then separated fromthe organic layer and extracted with ethyl acetate (×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, and the resultingmixture was vacuum filtered through a coarse fritted glass funnel. Thefiltrate was concentrated in vacuo to afford the crude product, whichwas purified by flash column chromatography on silica gel with 70:30 to50:50 hexanes-ethyl acetate gradient elution to afford 205a (157 mg,41%) as a white solid.

Analytical Data for 205a:

TLC (SiO₂) R_(f)=0.21 (hexanes:ethyl acetate-60:40); [α]₅₈₉^(T)=+31.8231 (c 0.605, CH₃OH); ¹H NMR (600 NMR, CD₃OD) δ 7.93 (d, J=9.1Hz, 1H), 7.16 (s, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.00 (dd, J=9.1, 2.3 Hz,1H), 4.50 (m, 1H), 3.06-2.97 (m, 2H), 2.93 (m, 1H), 2.14 (dd, J=12.4,7.3 Hz, 1H), 2.08-1.96 (m, 3H), 1.76 (td, J=11.7, 8.0 Hz, 1H), 1.30 (dd,J=12.3, 5.9 Hz, 1H), 0.54 (s, 3H); ¹³C NMR (150 MHz, CD₃OD) δ 155.98,137.59, 134.91, 128.83, 128.76, 125.38, 124.90, 119.92, 117.65, 105.00,71.05, 49.76, 48.03, 47.89, 47.75, 47.61, 47.46, 47.40, 47.32, 47.18,40.91, 36.33, 35.61, 24.10, 16.45; IR (thin film, cm⁻¹) 3398, 2927,2859, 1585, 1565, 1552, 1528, 1511, 1481, 1426; HRMS (ESI-TOF) m/z:[M+H] Calculated for C₁₈H₂₀O₂Br 347.0647; Found 347.0657.

3E. Steroid 205b

This Example describes the production of steroid 205b.

Synthesis of Steroid 205b:

To a stirring mixture of steroid 205a (30 mg, 0.086 mmol) in 0.6 mL MeOHand 0.15 mL DCM under nitrogen atmosphere was added 10% Pd/C (8.8 mg,0.0086 mmol) at room temperature. A balloon was used to introduce anatmosphere of hydrogen gas into the flask (allowing first for exchangeof the nitrogen atmosphere), and the reaction was stirred under aslightly positive pressure of hydrogen for approximately 8 h. Themixture was filtered through a cotton pipet and rinsed with DCM. Theresulting solution was concentrated in vacuo to afford the crudeproduct, which was purified by flash column chromatography on silica gelwith 70:30 to 60:40 hexanes-ethyl acetate gradient elution to affordsteroid 205b (19 mg, 77%) as a white solid.

Analytical Data for 205b:

TLC (SiO₂) R_(f)=0.20 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+51.374(c 0.890, CH₃OH); ¹H NMR (600 NMR, CD₃OD) δ 7.55 (d, J=8.8 Hz, 1H), 7.43(d, J=8.3 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.90 (dd, J=8.6, 2.8 Hz, 2H),4.51 (q, J=7.3, 6.7 Hz, 1H), 3.10-3.01 (m, 2H), 2.98 (dt, J=17.9, 9.0Hz, 1H), 2.14 (dd, J=12.3, 7.3 Hz, 1H), 2.12-2.03 (m, 2H), 2.01 (dd,J=12.7, 7.1 Hz, 1H), 1.79 (td, J=11.7, 8.1 Hz, 1H), 1.31 (dt, J=11.2,5.6 Hz, 1H), 0.55 (s, 3H); ¹³C NMR (150 MHz, CD₃OD) δ 155.03, 136.37,133.44, 129.72, 128.18, 127.05, 125.53, 121.50, 116.26, 104.47, 71.21,49.92, 48.04, 47.90, 47.75, 47.69, 47.63, 47.61, 47.47, 47.33, 47.19,40.95, 36.50, 35.89, 24.06, 16.51; IR (thin film, cm⁻¹) 3421, 2948,2937, 2921, 2983, 2854, 1623, 1516, 1436, 1375, 1364, 1335, 835; HRMS(ESI-TOF) m/z: [M+H] Calculated for C₁₈H₂₁O₂ 269.1542; Found 269.1534.

3F. Steroid 205c

This Example describes the production of steroid 205c.

Synthesis of Steroid 205c:

To a Schlenk tube containing 205a (20 mg, 0.058 mmol), Pd(PPh₃)₂Cl₂(2.03 mg, 0.0029 mmol) and CuI (1.1 mg, 0.0058 mmol) under nitrogenatmosphere at room temperature was added anhydrous triethylamine (16 μL,0.1152 mmol) and anhydrous DMF (2 mL) followed by phenylacetylene (12μL, 0.1152 mmol). The reaction mixture was stirred at 80° C. overnight(approximately 15 h). The resulting mixture was concentrated in vacuo,and DMF was removed by dissolving the mixture in diethyl ether andextracting it with water. The organic layer was then concentrated invacuo to afford the crude product, which was purified by flash columnchromatography on silica gel with 60:40 hexanes-ethyl acetate to affordsteroid 5c (18 mg, 84%) as a yellow solid.

Analytical Data for 205c:

TLC (SiO₂) R_(f)=0.20 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+26.178(c 0.105, CHCl₃); ¹H NMR (600 NMR, CDCl₃) δ 8.34 (d, J=8.9 Hz, 1H),7.73-7.53 (m, 2H), 7.49-7.31 (m, 4H), 7.28 (d, J=2.5 Hz, 1H), 7.14 (dd,J=8.9, 2.5 Hz, 1H), 5.15 (br s, 1H), 4.78-4.67 (m, 1H), 3.20 (dd,J=18.0, 7.9 Hz, 2H), 3.12 (m, 1H), 2.32 (dd, J=12.4, 7.3 Hz, 1H),2.28-2.17 (m, 2H), 2.13 (dd, J=12.7, 7.5 Hz, 1H), 1.92 (td, J=11.7, 7.7Hz, 1H), 1.44 (dd, J=12.5, 5.7 Hz, 1H), 0.66 (s, 3H); ¹³C NMR (150 MHz,CDCl₃) δ 153.86, 136.79, 131.61, 130.68, 128.95, 128.41, 128.23, 127.27,127.18, 123.54, 118.62, 116.94, 105.97, 93.50, 88.05, 77.10, 76.89,72.28, 50.61, 47.76, 41.43, 37.24, 35.88, 29.71, 24.72, 17.76; IR (thinfilm, cm⁻¹) 3421, 3237, 2973, 2916, 2852, 1717, 1698, 1682, 1658, 1647,1635, 1619, 1558, 1223; HRMS (ESI-TOF) m/z: [M+H] Calculated forC₂₆H₂₅O₂ 369.1855; Found 369.1837.

3G. Steroid 206a

This Example describes the production of steroid 206a used in subsequentreactions.

Synthesis of Steroid 206a:

To a solution of steroid 201a (800 mg, 2.21 mmol) in THF (6 mL) wassubsequently added formic acid (0.167 mL, 4.43 mmol), PPh₃ (1.162 g,4.43 mmol) and DIAD (0.872 mL, 4.43 mmol) (dropwise) at 0° C. Thereaction mixture was stirred for about 10 mins at 0° C., and then warmedto room temperature. It was continued to stir at room temperature forabout an hour. The resulting solution was concentrated in vacuo toafford the crude intermediate, which was purified by flash columnchromatography on silica gel with 90:10 to 70:30 hexanes-ethyl acetategradient elution to afford the intermediate as a yellow oil.

To a solution of the intermediate (720 mg, 1.85 mmol) in THF (2 mL) andMeOH (3 mL) was added K₂CO₃ (513 mg, 3.71 mmol) at room temperature. Thereaction mixture was stirred for 2 h and K₂CO₃ was removed by filteringthrough a cotton pipet. The resulting solution was then concentrated invacuo to afford the crude product, which was purified by flash columnchromatography on silica gel with 80:20 to 60:40 hexanes-ethyl acetategradient elution to afford steroid 206a (673 mg, 84% over 2 steps) as awhite solid.

Analytical Data for 206a:

TLC (SiO₂) R_(f)=0.32 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+37.071(c 0.560, CHCl₃); ¹H NMR (600 NMR, CDCl₃) δ 8.16-8.10 (m, 1H), 7.36 (s,1H), 7.21-7.16 (m, 2H), 4.68 (qd, J=6.5, 5.7, 2.8 Hz, 1H), 3.94 (s, 3H),3.21-3.05 (m, 2H), 2.81-2.69 (m, 2H), 2.13 (ddd, J=12.7, 6.6, 2.4 Hz,1H), 1.88-1.71 (m, 4H), 0.91 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 158.17,137.63, 134.59, 129.46, 129.45, 126.49, 125.79, 120.49, 118.08, 102.26,72.42, 55.36, 49.90, 49.36, 40.01, 37.02, 35.99, 24.57, 18.05; IR (thinfilm, cm⁻¹) 3410, 2946, 2920, 2858, 2848, 1623, 1464, 1451, 1428, 1373,1343, 1272, 1227, 1032; HRMS (ESI-TOF) m/z: [M+H] Calculated forC₁₉H₂₂O₂Br 361.0803; Found 361.0818.

3H. Steroid 206b

This Example describes the production of steroid 206b.

Synthesis of Steroid 206b:

To a stirring mixture of steroid 206a (17 mg, 0.055 mmol) in 2 mL ofanhydrous toluene under nitrogen atmosphere was added t-BuLi (1.58 M intoluene, 87 μL, 0.138 mmol) dropwise at 0° C. The reaction mixture wasstirred for an hour at 0° C. and warmed to room temperature. It wascontinued to stir at room temperature for an hour until it was quenchedwith DI water. The aqueous layer was separated from the organic layerand extracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄, and the resulting mixture was vacuum filteredthrough a coarse fritted glass funnel. The filtrate was concentrated invacuo to afford the crude product, which was purified by flash columnchromatography on silica gel with 80:20 to 60:40 hexanes-ethyl acetategradient elution to afford 206b (13 mg, 83%) as a white solid.

Analytical Data for 206b:

TLC (SiO₂) R_(f)=0.33 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=(c xxx,CHCl₃) In progress; ¹H NMR (600 NMR, CDCl₃) δ 7.72 (d, J=8.8 Hz, 1H),7.61 (d, J=8.3 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.15-7.03 (m, 2H),4.75-4.63 (m, 1H), 3.94 (s, 3H), 3.26-3.11 (m, 2H), 2.89-2.74 (m, 2H),2.14 (m, 1H), 1.92-1.82 (m, 1H), 1.83-1.70 (m, 3H), 0.96-0.88 (m, 3H));¹³C NMR (150 MHz, CDCl₃) δ 157.70, 136.52, 133.08, 130.12, 129.31,127.46, 125.79, 122.57, 116.95, 101.87, 72.61, 55.26, 50.10, 49.62,40.03, 37.14, 37.03, 36.21, 24.53, 18.12; IR (thin film, cm⁻¹) 3295,3050, 3002, 2955, 2941, 2917, 2892, 2871, 2838, 2824, 1621, 1430, 1415,1335, 1307, 1153, 1134, 1029, 835, 754, 720, 701; HRMS (ESI-TOF) m/z:[M+H] Calculated for C₁₉H₂₃O₂ 283.1698; Found 283.1688.

3I. Steroid 206c

This Example describes the production of steroid 206c.

Synthesis of Steroid 206c:

To a Schlenk tube containing 206a (20 mg, 0.0553 mmol), Pd(PPh₃)₂Cl₂(1.94 mg, 0.0027 mmol) and CuI (1.05 mg, 0.00553 mmol) under nitrogenatmosphere at room temperature was added anhydrous triethylamine (15 μL,0.1107 mmol) and anhydrous DMF (2 mL) followed by phenylacetylene (12μL, 0.1107 mmol). The reaction mixture was stirred at 80° C. overnight(approximately 15 h). The resulting mixture was concentrated in vacuo,and DMF was removed by dissolving the mixture in diethyl ether andextracting with water. The organic layer was then concentrated in vacuoto afford the crude product, which was purified by flash columnchromatography on silica gel with 70:30 to 60:40 hexanes-ethyl acetateto afford steroid 206c (15.3 mg, 81%) as a yellow solid.

Analytical Data for 206c:

TLC (SiO₂) R_(f)=0.30 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+15.556(c 0.295, CHCl3); ¹H NMR (600 NMR, CDCl₃) δ 8.35 (d, J=9.2 Hz, 1H), 7.64(dd, J=8.1, 1.4 Hz, 2H), 7.50-7.27 (m, 4H), 7.21 (d, J=8.6 Hz, 2H), 4.69(t, J=7.6 Hz, 1H), 3.95 (s, 3H), 3.22 (m, 2H), 2.91-2.71 (m, 2H), 2.15(ddd, J=12.6, 6.6, 2.0 Hz, 1H), 1.95-1.81 (m, 2H), 1.81-1.69 (m, 2H),1.65 br (s, 1H), 0.92 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 158.02,136.34, 133.12, 131.61, 130.96, 128.48, 128.40, 128.20, 127.23, 127.06,123.59, 118.51, 117.62, 102.27, 93.44, 88.16, 72.55, 55.30, 50.00,49.41, 39.98, 37.12, 36.10, 24.75, 18.10; IR (thin film, cm⁻¹) 3477,3059, 2979, 2952, 2935, 2904, 2853, 1770, 1759, 1747, 1718, 1685, 1663,1636, 1618, 1581, 1455, 1429, 1418, 1373, 1337, 1301, 1268, 1048, 1027,821, 762, 690; HRMS (ESI-TOF) m/z: [M+H] Calculated for C₂₇H₂₇O₂383.2011; Found 383.2023.

3J. Steroid 207a

This Example describes the production of steroid 207a used in subsequentreactions.

Synthesis of Steroid 207a:

To a solution of steroid 206a (80 mg, 0.221 mmol) in anhydrous toluene(2.2 mL) was added DIBALH (1.0 M in toluene, 2.2 mL, 2.21 mmol). Thereaction mixture was refluxed at 100° C. overnight (approximately 15 h).After the resulting solution was cooled to room temperature, it wasquenched by the careful addition of Rochelle's salt and stirred forabout 30 mins. The aqueous layer was then separated from the organiclayer and extracted with ethyl acetate (×3). The combined organic layerswere dried over anhydrous Na₂SO₄, and the resulting mixture was vacuumfiltered through a coarse fritted glass funnel. The filtrate wasconcentrated in vacuo to afford the crude product, which was purified byflash column chromatography on silica gel with 70:30 to 50:50hexanes-ethyl acetate gradient elution to afford 207a (50 mg, 65%) as awhite solid.

Analytical Data for 207a:

TLC (SiO₂) R_(f)=0.22 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=−885.25(c 0.105, (CD₃)₂SO); ¹H NMR (600 NMR, CDCl₃) δ 10.00 (s, 1H), 7.95 (d,J=9.0 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J=2.2 Hz, 1H), 7.15 (dd, J=9.1,2.3 Hz, 1H), 4.75 (s, 1H), 4.41 (t, J=7.2 Hz, 1H), 2.96 (m, 2H),2.68-2.54 (m, 2H), 2.03-1.91 (m, 1H), 1.64 (m, 2H), 1.56 (d, J=12.7 Hz,1H), 1.51 (m, 1H), 0.77 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 156.69,138.14, 135.16, 129.28, 129.15, 125.76, 124.46, 120.04, 119.08, 105.76,70.54, 49.87, 48.84, 36.96, 35.85, 24.42, 18.21; IR (thin film, cm⁻¹)3388, 2953, 2926, 2858, 1728, 1698, 1659, 1623, 1587, 1465, 1430, 1369,1161,1132,1024, 984, 888, 860, 833, 814; HRMS (ESI-TOF) m/z: Sample wassent out, but the mass did not match.

3K. Steroid 207b

This Example describes the production of steroid 207b.

Synthesis of Steroid 207b:

To a stirring mixture of steroid 207a (20 mg, 0.0576 mmol) in 1 mL MeOHand 0.25 mL DCM under nitrogen atmosphere was added 10% Pd/C (6.1 mg,0.0058 mmol) at room temperature. A balloon was used to introduce anatmosphere of hydrogen gas into the flask (allowing first for exchangeof the nitrogen atmosphere), and the reaction was stirred under aslightly positive pressure of hydrogen for approximately 8 h. Themixture was filtered through a cotton pipet and rinsed with DCM. Theresulting solution was concentrated in vacuo to afford the crudeproduct, which was purified by flash column chromatography on silica gelwith 65:35 hexanes-ethyl acetate to afford steroid 207b (12.2 mg, 79%)as a white solid.

Analytical Data for 207b:

TLC (SiO₂) R_(f)=0.23 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=+36.368(c 0.310, CD₃OD); ¹H NMR (600 NMR, CD₃OD) δ 7.56 (d, J=8.8 Hz, 1H), 7.45(d, J=8.3 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.99-6.82 (m, 2H), 4.50 (q,J=6.6, 6.0 Hz, 1H), 3.02 (m, 2H), 2.74-2.57 (m, 2H), 2.00 (ddd, J=12.5,6.3, 2.4 Hz, 1H), 1.72 (dd, J=13.2, 8.6 Hz, 1H), 1.69-1.58 (m, 3H), 0.78(s, 3H); ¹³C NMR (150 MHz, CD₃OD) δ 155.03, 136.11, 133.48, 129.71,128.23, 127.05, 125.48, 121.42, 116.25, 104.42, 71.46, 49.06, 49.01,39.63, 36.31, 36.06, 23.97, 16.97; IR (thin film, cm⁻¹) 3404, 3040,2950, 2915, 2870, 2855, 1656, 1638, 1623, 1434, 1367, 1329, 1135, 1027,835; HRMS (ESI-TOF) m/z: [M+H] Calculated for C₁₈H₂₁O₂ 269.1542; Found269.1553.

3L. Steroid 207c

This Example describes the production of steroid 207c.

Synthesis of Steroid 207c:

To a Schlenk tube containing 207a (20 mg, 0.058 mmol), Pd(PPh₃)₂Cl₂(2.03 mg, 0.0029 mmol) and CuI (1.1 mg, 0.0058 mmol) under nitrogenatmosphere at room temperature was added anhydrous triethylamine (16 μL,0.1152 mmol) and anhydrous DMF (2 mL) followed by phenylacetylene (12μL, 0.1152 mmol). The reaction mixture was stirred at 80° C. overnight(approximately 15 h). The resulting mixture was concentrated in vacuo,and DMF was removed by dissolving the mixture in diethyl ether andextracting with water. The organic layer was then concentrated in vacuoto afford the crude product, which was purified by flash columnchromatography on silica gel with 65:35 hexanes-ethyl acetate to affordsteroid 207c (18.3 mg, 85%) as a yellow solid.

Analytical Data for 207c:

TLC (SiO₂) R_(f)=0.24 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=(c0.145, (CH₃)₃CO); ¹H NMR (600 NMR, (CD₃)₂SO) δ 9.88 (d, J=1.5 Hz, 1H),8.19 (d, J=8.9 Hz, 1H), 7.67 (d, J=7.3 Hz, 2H), 7.54-7.35 (m, 3H), 7.25(s, 1H), 7.22 (s, 1H), 7.16 (dd, J=8.9, 2.4 Hz, 1H), 4.76 (dd, J=4.0,1.9 Hz, 1H), 4.53-4.40 (m, 1H), 3.15-2.97 (m, 2H), 2.75-2.63 (m, 2H),2.03 (dd, J=12.4, 7.4 Hz, 1H), 1.77-1.65 (m, 2H), 1.65-1.51 (m, 2H),0.80 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ; IR (thin film, cm⁻¹) 3415,3226, 1669, 1641, 1623; HRMS (ESI-TOF) m/z: [M+H] Calculated forC₂₆H₂₅O₂ 369.1855; Found 369.1837.

3M. Steroid 208a

This Example describes the production of steroid 208a.

Synthesis of Steroid 208a:

See Zajc, B. J. Org. Chem. 1999, 64, 1902-1907. To a stirring solutionof TBS-protected 201a (50 mg, 0.105 mmol) in anhydrous toluene (2.3 mL)at 0° C. was added t-BuLi (1.58 M in toluene, 0.12 mL, 0.21 mmol). Afterthe reaction mixture was stirred for about an hour at 0° C., NFSi (66mg, 0.21 mmol) in toluene (1.3 mL) was added to the flask. The ice bathwas removed after the addition of NFSi, and the resulting mixture wasstirred for 2 hours at room temperature. The reaction mixture wasquenched with saturated aqueous NH₄Cl, and the aqueous layer wasseparated from the organic layer and extracted with ethyl acetate (×3).The combined organic layers were dried over anhydrous Na₂SO₄, and theresulting mixture was vacuum filtered through a coarse fritted glassfunnel. The filtrate was concentrated in vacuo to afford the crudeproduct.

To a solution of the above product (17 mg, 0.041 mmol) in anhydrous THF(2 mL) was added TBAF (13 μL, 0.045 mmol) at 0° C. The mixture wasstirred for an hour at 0° C., warmed up to room temperature and stirredat room temperature for 2 h. It was quenched with saturated aqueousNH₄Cl, and the aqueous layer was separated from the organic layer andextracted with diethyl ether (×3). The combined organic layers weredried over anhydrous Na₂SO₄, and the resulting mixture was vacuumfiltered through a coarse fritted glass funnel. The filtrate wasconcentrated in vacuo to afford the crude product, which was purified byflash column chromatography on silica gel with 70:30 to 50:50hexanes-ethyl acetate gradient elution to afford 208a (8 mg, 65%) as awhite solid.

Analytical Data for 208a:

TLC (SiO₂) R_(f)=0.28 (hexanes:ethyl acetate-65:35); [α]₅₈₉ ^(T)=(c xxx,CHCl₃) In progress; ¹H NMR (600 NMR, CDCl₃) δ 7.99 (d, J=8.9 Hz, 1H),7.18-7.09 (m, 2H), 6.74 (d, J=11.1 Hz, 1H), 4.78-4.63 (m, 1H), 3.93 (s,3H), 3.26-3.02 (m, 3H), 2.31 (dd, J=12.5, 7.3 Hz, 1H), 2.20-2.09 (m,3H), 1.91 (td, J=11.8, 7.8 Hz, 1H), 1.47-1.40 (m, 1H), 0.66 (s, 3H); ¹³CNMR (150 MHz, CDCl₃) δ In progress; IR (thin film, cm⁻¹) In progress;HRMS (ESI-TOF) m/z: [M+H] Calculated for C₁₉H₂₂O₂F 301.1604; Found301.1615.

3N. Steroid 208b

This Example describes the production of steroid 208b.

Synthesis of Steroid 208b:

To a solution of 208a (30 mg, 0.0998 mmol) in anhydrous toluene (1 mL)at room temperature was added DIBALH (1.0 M in toluene, 0.998 mL, 0.998mmol). The reaction mixture was refluxed at 100° C. overnight(approximately 15 h). After the resulting solution was cooled to roomtemperature, it was quenched by the careful addition of Rochelle's saltand stirred for about 30 mins. The aqueous layer was then separated fromthe organic layer and extracted with ethyl acetate (×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, and the resultingmixture was vacuum filtered through a coarse fritted glass funnel. Thefiltrate was concentrated in vacuo to afford the crude product, whichwas purified by flash column chromatography on silica gel with 70:30 to50:50 hexanes-ethyl acetate gradient elution to afford 208b (18 mg, 64%)as a yellow oil.

Analytical Data for 208b:

TLC (SiO₂) R_(f)=0.21 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=(c xxx,CD₃OD) In progress; ¹H NMR (600 NMR, CDCl₃) δ 7.79 (d, J=8.9 Hz, 1H),7.10 (t, J=2.1 Hz, 1H) 6.97 (dd, J=9.0, 2.3 Hz, 1H), 6.57 (d, J=11.4 Hz,1H), 4.56-4.44 (m, 1H), 3.09-2.85 (m, 3H), 2.13 (dd, J=12.4, 7.3 Hz,1H), 2.08-1.94 (m, 3H), 1.76 (td, J=11.8, 7.9 Hz, 1H), 1.31 (dd, J=12.4,5.8 Hz, 1H), 0.54 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ In progress; IR(thin film, cm⁻¹) In progress; HRMS (ESI-TOF) m/z: [M+H] Calculated forC₁₈H₂₀O₂F 287.1447; Found 287.1447.

3O. Steroid 208c

This Example describes the production of steroid 208c.

Synthesis of Steroid 208c:

To a solution of steroid 208a (117 mg, 0.3895 mmol) in THF (4 mL) wassubsequently added formic acid (29 μL, 0.779 mmol), PPh₃ (204 mg, 0.779mmol) and DIAD (0.15 mL, 0.779 mmol) (dropwise) at 0° C. The reactionmixture was stirred for about 10 mins at 0° C., and then warmed to roomtemperature. It was continued to stir at room temperature for about anhour. The resulting solution was concentrated in vacuo to afford thecrude intermediate, which was purified by flash column chromatography onsilica gel with 95:5 to 90:10 hexanes-ethyl acetate gradient elution toafford the intermediate as a yellow oil.

To a solution of the intermediate (100 mg, 0.305 mmol) in THF (2 mL) andMeOH (3 mL) was added K₂CO₃ (84 mg, 0.609 mmol) at room temperature. Thereaction mixture was stirred for 2 h and K₂CO₃ was removed by filteringthrough a cotton pipet. The resulting solution was then concentrated invacuo to afford the crude product, which was purified by flash columnchromatography on silica gel with 80:20 to 60:40 hexanes-ethyl acetategradient elution to afford steroid 208c (53.5 mg, 46% over 2 steps) as awhite solid.

Analytical Data for 208c:

TLC (SiO₂) R_(f)=0.25 (hexanes:ethyl acetate-60:40); [α]₅₈₉ ^(T)=(c xxx,CHCl₃) In progress; ¹H NMR (600 NMR, CDCl₃) δ 7.99 (d, J=9.0 Hz, 1H),7.18-7.12 (m, 2H), 6.76 (d, J=11.2 Hz, 1H), 4.68 (q, J=7.4 Hz, 1H), 3.94(s, 3H), 3.26-3.05 (m, 2H), 2.84-2.77 (m, 1H), 2.74 (dt, J=12.1, 7.3 Hz,1H), 2.13 (ddd, J=12.7, 6.8, 2.3 Hz, 1H), 1.86 (dd, J=13.5, 8.3 Hz, 1H),1.82-1.69 (m, 3H), 0.91 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ In progress;IR (thin film, cm⁻¹) In progress; HRMS (ESI-TOF) m/z: [M+H] Calculatedfor C₁₉H₂₂O₂F 301.1604; Found 301.1606.

3P. Steroid 209

This Example describes the production of steroid 209 used in subsequentreactions.

Synthesis of Steroid 209:

To a stirring solution of DMSO (0.45 mL) and DCM (20 mL) at −78° C. wasadded oxalyl chloride (0.27 mL, 2.17 mmol). The solution was stirred forabout 5 mins, and steroid 201a (954 mg, 2.64 mmol) in DCM (20 mL) wasadded. The reaction mixture was stirred at −78° C. for 2 hr and quenchedwith saturated aqueous NaHCO₃. The aqueous layer was separated from theorganic layer and extracted with ethyl acetate (×3). The combinedorganic layers were dried over anhydrous MgSO₄, and the resultingmixture was vacuum filtered through a coarse fritted glass funnel. Thefiltrate was concentrated in vacuo to afford the crude product, whichwas purified by flash column chromatography on silica gel with 80:20hexanes-ethyl acetate to afford steroid 209 (524 mg, 55%) as a yellowsolid.

Analytical Data for 209:

¹H NMR (600 NMR, CDCl₃) δ 8.16 (d, J=9.1 Hz, 1H), 7.27 (s, 1H),7.25-7.18 (m, 2H), 3.96 (s, 3H), 3.38 (dd, J=13.6, 7.7 Hz, 1H),3.28-3.14 (m, 2H), 2.78 (dd, J=17.7, 7.8 Hz, 1H), 2.49-2.41 (m, 1H),2.39 (d, J=16.7 Hz, 1H), 2.28 (ddd, J=12.8, 7.3, 1.7 Hz, 1H), 2.23 (d,J=16.9 Hz, 1H), 2.05 (td, J=11.5, 8.3 Hz, 1H), 0.82 (s, 3H)

3Q. Steroid 210

This Example describes the production of steroid 210 used in subsequentreactions.

Synthesis of Steroid 210:

A catalyst solution containing conc. H₂SO₄ (0.1 mL) and isopropenylacetate (5 mL) was prepared and stored under nitrogen. To a solution of209 (524 mg, 1.508 mmol) in isopropenyl acetate (13 mL) at roomtemperature was added 0.26 mL of the catalyst solution. The resultingmixture was stirred for 2.5 hr at 100° C., and then cooled to roomtemperature, at which point another portion of the catalyst solution(0.26 mL) was added. The reaction mixture was then stirred for 2.5 hr at100° C. and quenched with saturated aqueous NaHCO₃. The aqueous layerwas separated from the organic layer and extracted with ethyl acetate(×3). The combined organic layers were dried over anhydrous Na₂SO₄, andthe resulting mixture was vacuum filtered through a coarse fritted glassfunnel. The filtrate was concentrated in vacuo to afford the crudeproduct, which was purified by flash column chromatography on silica gelwith 85:15 hexanes-ethyl acetate to afford steroid 210 (275 mg, 45%,(64% brsm)) as a white solid.

Analytical Data for 210:

¹H NMR (600 NMR, CDCl₃) δ 8.15 (d, J=9.1 Hz, 1H), 7.34 (s, 1H),7.22-7.13 (m, 2H), 5.72 (s, 1H), 3.94 (s, 3H), 3.40 (dd, J=11.7, 7.2 Hz,1H), 3.25-3.16 (m, 1H), 3.12 (dd, J=17.9, 8.6 Hz, 1H), 2.88-2.78 (m,1H), 2.70 (dd, J=14.2, 7.1 Hz, 1H), 2.19 (s, 3H), 2.16-2.10 (m, 1H),2.11-2.02 (m, 1H), 0.76 (s, 3H)

3R. Steroid 211

This Example describes the production of steroid 211 used in subsequentreactions.

Synthesis of Steroid 211:

To a solution of 210 (274 mg, 0.683 mmol) in CCl₄ (13 mL) was added asolution of Br₂ (0.11 mL, 0.683 mmol) in CHCl₃ (2.28 mL) at −10° C. Thereaction mixture was stirred for 20 mins at −10° C. and quenched withsaturated aqueous Na₂S₂O₃. The aqueous layer was separated from theorganic layer and extracted with DCM (×3). The combined organic layerswere dried over anhydrous Na₂SO₄, and the resulting mixture was vacuumfiltered through a coarse fritted glass funnel. The filtrate wasconcentrated in vacuo to afford the crude product, which was purified byflash column chromatography on silica gel with 90:10 hexanes-ethylacetate to afford steroid 211 (214 mg, 72%) as a white solid.

Analytical Data for 211:

¹H NMR (600 NMR, CDCl₃) δ 8.17 (d, J=9.2 Hz, 1H), 7.27 (s, 1H), 7.23(dd, J=9.2, 2.4 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 4.16 (s, 1H), 3.96 (s,3H), 3.80 (dd, J=12.6, 8.3 Hz, 1H), 3.28 (dd, J=17.8, 7.8 Hz, 1H),3.20-3.09 (m, 1H), 2.95 (dd, J=18.4, 8.3 Hz, 1H), 2.42 (ddd, J=18.4,12.6, 1.0 Hz, 1H), 2.34 (td, J=12.0, 7.8 Hz, 1H), 2.10-2.05 (m, 1H),0.95 (s, 3H)

3S. Steroid 212

This Example describes the production of steroid 212 used in subsequentreactions.

Synthesis of Steroid 212:

To a solution of 211 (60 mg, 0.186 mmol) in acetic acid (1.5 mL) andacetic anhydride (0.12 mL) was added Pb(OAc)₄ (165 mg, 0.372 mmol) atroom temperature. After the reaction mixture was stirred for 5 hours, itwas quenched with saturated aqueous NaHCO₃. The aqueous layer wasseparated from the organic layer and extracted with ethyl acetate (×3).The combined organic layers were dried over anhydrous Na₂SO₄, and theresulting mixture was vacuum filtered through a coarse fritted glassfunnel. The filtrate was concentrated in vacuo to afford the crudeproduct, which was purified by flash column chromatography on silica gelwith 93:7 to 70:30 hexanes-ethyl acetate gradient elution to affordsteroid 212 (25 mg, 37%, 7:1 dr) as a white solid.

Analytical Data for 212:

¹H NMR (600 NMR, CDCl₃) δ 8.17 (d, J=8.9 Hz, 1H), 7.40 (s, 1H), 7.19(dd, J=9.3, 2.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.80 (dd, J=9.0, 5.3Hz, 1H), 5.68 (d, J=2.0 Hz, 1H), 3.88 (s, 3H), 3.66 (dd, J=11.6, 7.1 Hz,1H), 2.89-2.78 (m, 2H), 2.77-2.70 (m, 1H), 2.19 (s, 4H), 2.05 (s, 4H),1.97 (dd, J=13.0, 5.4 Hz, 1H), 0.66 (s, 3H)

Example 4: Further Reactions with Steroids

4A. Non-Aromatic A Ring Formation

This Example describes the production of steroid 37 used in subsequentreactions.

Briefly, a solution of steroid 15 (14 mg, 0.044 mmol, 1.0 equiv) andt-BuOH (26 mg, 0.35 mmol, 8.0 equiv) in 1 mL THF followed by lithiummetal (31 mg, 4.4 mmol, 100.0 equiv) was added to a Schlenk tube chargedwith 4 mL liq. NH₃ under N₂ atmosphere at −78° C. The resulting mixturewas stirred at −78° C. for 1 h, and NH₄Cl (s) was added. The coolingbath was removed, and the reaction mixture was slowly warmed to rt. 3 mL3 M HCl (aq) was added to the reaction mixture, stirred for 30 min, and10 mL ethyl acetate was added. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with water, sat. NaHCO₃ (aq), brine, and thendried over anhydrous MgSO₄. The resulting suspension was filteredthrough a coarse fritted glass funnel, and the filtrate was concentratedin vacuo. Purification of the crude product by flash columnchromatography afforded 5.9 mg of compound steroid 37 as a yellow film(50%).

4B. Regioselective Enolization & Formation of Enolacetate 38

This Example describes the production of ketone S21 used in subsequentreactions and the production of the steroidal enolacetate 38.

To a stirring solution of steroid 27 (0.13 g, 0.34 mmol, 1.0 equiv) in 3mL CH₂Cl₂ was added DMP (0.43 g, 1.0 mmol, 3.0 equiv). The mixture wasstirred until the reaction was judged to be complete by TLC analysis,then partitioned between 10 mL of sat. NaHCO₃ (aq) and 30 mL CH₂Cl₂. Theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (50 mL×2). The combined organic layers were dried over anhydrousMgSO₄, filtered through a coarse fritted glass funnel, and the filtratewas concentrated in vacuo. Purification of the crude product by flashcolumn chromatography afforded 0.11 g of compound ketone S21 as acolorless film (85%).

To a solution of ketone S21 (0.11 g, 0.29 mmol, 1.0 equiv) in 2.5 mLisopropenyl acetate at rt under N₂ atmosphere was added 50 μL of 2%conc. H₂SO₄ (aq) in isopropenyl acetate. The resulting brown solutionwas warmed to 100° C. and stirred for 2.5 hr. Then, the solution wascooled to rt and another 50 μL of 2% conc. H₂SO₄ (aq) in isopropenylacetate was added. The resulting mixture was further stirred at 100° C.until the reaction was complete based on TLC analysis, then partitionedbetween 10 mL sat. NaHCO₃ (aq) and 20 mL ethyl acetate. The organiclayer was separated, and the aqueous layer was extracted with ethylacetate (20 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered through a coarse fritted glass funnel, and the filtratewas concentrated in vacuo. Purification of the crude product by flashcolumn chromatography afforded 51 mg of compound 38 as a white amorphoussolid (42%).

4C. B-Ring Functionalization

This Example describes the production of steroid 39 used in subsequentreactions.

Pd(dppf)Cl₂ (5.8 mg, 0.0080 mmol, 0.050 equiv), KOAc (30.0 mg, 0.30mmol, 2.0 equiv), bis(pinacolato)diboron (46 mg, 0.18 mmol, 1.2 equiv)and ent-12 (50.0 mg, 0.15 mmol, 1.0 equiv) were added to a Schlenk tubeequipped with a magnetic stir bar. The reaction vessel was evacuatedwith vacuum and backfilled with nitrogen 3 times, and then 2 mL dioxanewas added. The resulting mixture was warmed to 110° C. and stirredovernight (approx. 12 h). The solution was cooled to rt, and 10 mL ethylacetate was added. The resulting mixture was passed through a pad ofcelite, and the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 32 mg of theborated product as a film (56%).

To a solution of the above borated compound (23 mg, 0.061 mmol, 1.0equiv) in 2 mL THF under N₂ atmosphere at rt was added NaBO₃.4H₂O (18mg, 0.12 mmol, 2 equiv). The resulting mixture was stirred at rt untilthe reaction was judged to be complete by TLC analysis, then partitionedbetween 5 ml sat. NH₄Cl (aq) and 5 mL ethyl acetate. The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate (5mL×3). The combined organic layers were washed with water, brine, anddried over anhydrous MgSO₄. The resulting suspension was filteredthrough a coarse fritted glass funnel, and the filtrate was concentratedin vacuo. Purification of the crude product by flash columnchromatography afforded 14 mg of compound S22 as a white amorphous solid(86%).

To a solution of steroid S22 (10.0 mg, 0.037 mmol, 1.0 equiv) in 2 mLCH₂Cl₂ under N₂ atmosphere at −78° C. was added a solution of PhI(OAc)₂(17.8 mg, 0.055 mmol, 1.5 equiv) in 0.1 mL CH₂Cl₂ dropwise. Theresulting mixture was stirred for 5 min at −78° C., then partitionedbetween 4 mL sat. NaHCO₃ (aq) and 3 mL CH₂Cl₂. The organic layer wasseparated, and the aqueous layer was extracted with CH₂Cl₂ (5 mL×2). Thecombined organic layers were washed with brine and dried over anhydrousMgSO₄. The resulting suspension was filtered through a coarse frittedglass funnel, and the filtrate was concentrated in vacuo. Purificationof the crude product by flash column chromatography afforded 4.9 mg ofcompound steroid 39 as a film (50%).

4D. Suzuki Coupling at C6

This Example describes the production of steroid 40 used in subsequentreactions.

Pd(PPh₃)₄ (1.7 mg, 0.0015 mmol, 0.05 equiv), K₂CO₃ (8.2 mg, 0.06 mmol, 2equiv), 4-methoxyphenylboronic acid (9.2 mg, 0.06 mmol, 2 equiv) andcompound steroid 12 (10 mg, 0.03 mmol, 1 equiv) were added to a Schlenktube equipped with a magnetic stir bar. The reaction vessel wasevacuated with vacuum and backfilled with nitrogen 3 times, and then 0.9overnight. The reaction mixture was cooled to rt, and (5 mL) ethylacetate was added. The Purification of the crude product by flash columnchromatography afforded 7.5 mg of compound steroid 40 as a film (70%).

4E. C11 Oxygenation

This Example describes the production of steroid 41 used in subsequentreactions.

CuI (1.7 mg, 0.009 mmol, 0.1 equiv), quinolin-8-ol (1.3 mg, 0.009 mmol,0.1 equiv), K₂CO₃ (25 mg, 0.182 mmol, 2 equiv) and ent-12 (30 mg, 0.091mmol, 1 equiv) were added to a Schlenk tube equipped with a magneticstir bar. The reaction vessel was evacuated with vacuum and backfilledwith nitrogen 3 times. Phenol (17 mg, 0.182 mmol, 2 equiv) and 1 mL DMFwas added, and the resulting mixture was stirred overnight at 130° C.(approx. 12 h). The reaction mixture was cooled to rt, and ethyl acetate(5 mL) was added. The resulting mixture was filtered through a pad ofcelite, and the filtrate was concentrated in vacuo. Purification of thecrude product by flash column chromatography afforded 21 mg of the S23as a film (68%).

To a solution of S23 (6 mg, 0.02 mmol) in 1 mL CH₃CN was added CAN (48mg, 0.087 mmol, 5.0 equiv) in 0.3 mL DI water at rt. The resultingsolution was stirred at rt for 30 min, then partitioned between 5 mLethyl acetate and 3 mL DI water. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with water, brine, and dried over anhydrousMgSO₄. The resulting suspension was filtered through a coarse frittedglass funnel, and the filtrate was concentrated in vacuo. Purificationof the crude product by flash column chromatography afforded 4.3 mg ofsteroid 41 as a film (48% over 2 steps).

Example 5: Multigram-Scale Preparation of Synthetic Steroid ent-12

5A. Steroid ent-12

This Example describes the production of steroid ent-12 used insubsequent reactions.

To a stirring solution of epoxide 42 (14.8 g, 0.0786 mol, 1.0 equiv) in300 mL THF under N₂ atmosphere at −78° C. was added CuI (3.0 g, 0.016mol, 0.2 equiv) followed by isopropenyl magnesium bromide (0.50 M inTHF, 0.19 L, 0.094 mol, 1.2 equiv). The resulting yellow suspension wasstirred for 1 h at −78° C., warmed to rt, and then stirred until thereaction was judged to be complete by TLC analysis. The reaction wasquenched by adding 200 mL sat. NH₄Cl (aq) to the reaction mixture. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (200 mL×3). The combined organic layers were dried overanhydrous MgSO₄, filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product bySiO₂ flash column chromatography using 20% ethyl acetate: 80% hexanes asthe eluent afforded 14.8 g of the enyne ent-6 as a yellow oil (81%).

To a stirring solution of alkyne 7 (30.0 g 0.172 mol, 2.7 equiv) in 1.2L of dry toluene at rt under N₂ atmosphere was added Ti(Oi-Pr)₄ (49.1 g,0.172 mmol 2.7 equiv). The resulting mixture was cooled to −78° C., andn-BuLi (2.7 M in hexanes, 135 mL, 0.364 mol, 5.7 equiv) was addeddropwise. The resulting black Ti-alkyne complex was warmed first to rt,then heated to 50° C. and stirred at 50° C. for 1 h (a reflux condenserwas not used). In a separate flask under N₂ atmosphere, enyne ent-6(14.7 g, 0.0638 mol, 1.0 equiv) was dissolved in 300 mL of dry toluene,cooled to −78° C., and treated with n-BuLi (2.5 M in hexanes, 25 mL,0.064 mmol, 1.0 equiv) dropwise at −78° C. The resulting yellow solutionwas warmed to rt, and then transferred by cannula to the black Ti-alkynecomplex at −78° C. The resulting mixture was slowly warmed to rtovernight (approx. 17 h). After this period, 1.5 L of dry MeOH in aseparate flask was cooled to −78° C. under N₂ atmosphere, and thereaction mixture was transferred by cannula to the pre-cooled MeOH. Oncethe addition was complete, the reaction mixture was warmed to rt, and500 mL of DI H₂O was added. The reaction mixture was further dilutedwith 500 mL ethyl acetate. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (500 mL×3). The combinedorganic layers were dried over anhydrous MgSO₄, filtered through acoarse fritted glass funnel, and then the filtrate was concentrated invacuo. Purification of the crude product by flash column chromatographyusing 25% ethyl acetate: 75% hexanes as the eluent afforded 12.4 g ofthe compounds steroid ent-8 and S5 as a yellow oil (60%, isolated as a4:1 mixture of ent-8:S5).

The following three-step procedure was used to convert 9.9 g of thetrans-fused hydrindane ent-8 to the steroidal product ent-12 with anoverall 40% isolated yield. This yield is based on the amount ofhydrindane ent-8 present in a 4:1 mixture with the unreactive “endo”diene isomer S5.

To a solution of 12.4 g of 4:1 mixture of hydrindane ent-8 (9.9 g, 0.030mol, 1.0 equiv) and its corresponding endo diene isomer S5 (2.5 g,0.0080 mol) in 500 mL THF was added TBSCI (11.4 g, 0.0756 mol, 2.5equiv) and imidazole (5.2 g, 0.076 mol, 2.5 equiv). The reaction mixturewas stirred at rt under N₂ atmosphere overnight (approx. 17 h), thenpartitioned between 200 mL sat. NaHCO₃ (aq) and 200 mL ethyl acetate.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate (200 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The resulting suspension wasfiltered through a coarse fritted glass funnel, and the filtrate wasconcentrated in vacuo. The crude product was passed through a pad ofsilica gel using 1% hexanes: 99% ethyl acetate as the eluent to afford15.8 g of the crude product as a yellow oil. The crude product was usedin the next step without further purification.

To a solution of the above crude product (15.8 g) and TEBAC (1.7 g, 7.3mmol) in 73 mL CHBr₃ at rt was added KOH (24.6 g, 0.438 mol) in water(25 mL). The reaction mixture was stirred at 45° C. overnight (approx.17 h). The reaction mixture was cooled to rt, then partitioned between100 mL DI water and 200 mL CH₂Cl₂. The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂ (200 mL×3). The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄.The resulting suspension was filtered through a coarse fritted glassfunnel, and the filtrate was concentrated in vacuo to afford 19.6 g ofthe crude product as a brown oil. The crude product was used in the nextstep without further purification.

To a solution of the above crude product (19.6 g) in 600 mL nitromethanewas added i-PrOH (20.4 g, 0.34 mol) and TiCl₄ (15.9 g, 0.084 mol). Theresulting mixture was stirred at rt for 1 h under N₂ atmosphere, and asecond aliquot of i-PrOH (20.4 g, 0.34 mol) and TiCl₄ (15.9 g, 0.084mol) was added. The mixture was stirred for another 1 h at rt under N₂atmosphere, then partitioned between 200 mL sat. NaHCO₃ (aq) and 200 mLCH₂Cl₂. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂ (200 mL×3). The combined organic layers werewashed with brine and dried over anhydrous MgSO₄. The resultingsuspension was filtered through a coarse fritted glass funnel, and thefiltrate was concentrated in vacuo. Purification of the crude product byflash column chromatography using 20% ethyl acetate: 80% hexanes as theeluent afforded 4.0 g of compound steroid ent-12 as a yellow amorphoussolid (40% over 3 steps).

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting of the invention described herein.

Example 6: In Vitro Growth Inhibition

Fifteen (15) exemplary compounds were investigated for growth inhibitionin two cancer cell lines (one for breast and one for pancreatic cancer:MDA-MB-231 and AsPC-1, respectively).

Procedure: Inhibition of cell growth was accessed by plating 1000 cellsper well of a 96-well plate. The following day, compounds were added as2-fold dilutions from 40 μM (8 wells/concentration). After 6 days, cellswere washed, lysed and stained with Hoechst 33258. Fluorescence was readon a microplate spectrofluorometer. Results are expressed as theconcentration that inhibited growth by 50% (GI₅₀). See Rao, J., Otto, W.R. Fluorometric DNA assay for cell growth estimation. Anal Biochem.1992; 207:186-192.

MDA-MB-231 AsPC-1 Compound GI₅₀ (μM) GI₅₀ (μM) 205b 0.8 2 201a 15 15201b 25 30 206a 20 20 201c 20 30 206c 15 15 205c 8 9 205a 17 10 208a 2530 206b 30 40 207b 20 40 207c 5 15 207a 30 30 208b 4 8 208c 5 25

Compound 205b has been identified as a uniquely potent and selectiveagonist of ER-β, having an EC₅₀=20 nM for ER-β and an EC₅₀ over 3000 nMfor ER-α. Compound 205b also has been found to have affinity to CLK-4 (amember of the family of CDC-2-like kinases at −350 nM. Growth of severalcancer cell lines (MDA-MB-231, AsPC-1, and A549) incubated with Compound205b was inhibited at 0.8-5 μM. Parallel experiments demonstrated thatthese concentrations arrested cells in G2/M phase of the cell cycle, andmicroscopic analysis showed the cells arrested in mitosis atprometaphase.

Compound 39 was also investigated for growth inhibition in three cancercell lines: MDA-MB-231, AsPC-1, and U2OS (human osteosarcoma). DNAfluorescence as a percent of control for increasing concentrations ofCompound 39 are shown in FIG. 3D. The calculated GI₅₀ for Compound 39against MDA-MB-231 was 0.32 ug/mL (1.2 uM) and the calculated GI₅₀ forCompound 39 against U2OS and AsPC-1 was ˜4 uM.

INCORPORATION BY REFERENCE

The contents of all cited references including literature references aswell as all foreign and patents and patent applications that are citedthroughout this application are hereby expressly incorporated byreference in their entirety, as are the references cited therein. Thepresent disclosure specifically incorporates U.S. Pat. Publication Nos:20020132802; 20050054624; 20060009438; 20150250801; 20150259376;20150361125; 20160326127; and U.S. Pat. Nos. 5,554,601; 5,843,934;5,877,169; 6,350,739; 6,503,894; 6,680,331; 6,844,456; 7,781,421;8,759,330; 9,156,876; 9,365,502; 9,388,210; 9,505,743; 9,512,170;9,562,026; 9,630,986; and 9,676,812, by reference in their entireties.

What is claimed is:
 1. A method for manufacturing a tetracycliccompound, the method comprising a step of: (a) reacting a compound ofFormula (Ci) with a compound of Formula (Di) to give a hydrindane ofFormula (Ei):

wherein LG is a leaving group; Cy is C₃₋₈-cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl; eachR^(M) is independently selected from the group consisting of hydrogen,C₁₋₆-alkyl, trimethylsilyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,arylalkyl, and —OR^(MX), wherein R^(MX) is hydrogen, C₁₋₆-alkyl, orC₆₋₁₀-aryl; n is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; m is an integer selected from 0, 1, and2; R^(A) is selected from the group consisting of hydrogen, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, halogen, hydroxy,—OR^(AX), —SR^(AY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1), —S(O)R^(Z1),—NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2), —N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl,and 5- to 10-membered heteroaryl, or two R^(A) together form an oxo,wherein R^(AX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl,—S(O)₂R^(Z1), C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl, whereinR^(AY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl,C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl, wherein each of R^(Z1) andR^(Z2) are independently hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, C₆₋₁₀-aryl, 5- to 10-memberedheteroaryl, hydroxy, or C₁₋₆-alkoxy; R¹³ is selected from the groupconsisting of C₁₋₆-alkyl and C₆₋₁₀-aryl-C₁₋₆-alkyl, wherein theC₆₋₁₀-aryl of R¹³ is optionally substituted one or more halogen,C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; and each R¹⁷ isindependently selected from the group consisting of hydrogen,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, and halogen,or two R¹⁷ together form an oxo, wherein any C₃₋₈-cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀-aryl or 5- to 10-membered heteroarylis optionally substituted with one or more halogen, C₁₋₆-alkyl,C₁₋₆-haloalkyl, or C₁₋₆-alkoxy; (b) treating the hydrindane of Formula(Ei) to install a carbon and provide a reactive intermediate for B-ringformation; and (c) performing an intramolecular ring-closing reaction toform the tetracyclic compound.
 2. The method of claim 1, wherein step(b) comprises cyclopropanation of the compound of Formula (Ei) to form acompound of Formula (Fi):

wherein X¹ and X² are independently selected from the group consistingof hydrogen, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl,halogen, oxygen, —OR^(Bx), —SR^(BY), —S(O)₂NR^(Z1)R^(Z2), —S(O)₂R^(Z1),—S(O)R^(Z1), —NR^(Z1)R^(Z2), —N(R^(Z1))C(O)R^(Z2),—N(R^(Z1))S(O)₂R^(Z2), C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₆₋₁₀-aryl-C₁₋₆-alkyl, C₆₋₁₀-aryl-C₂₋₆-alkenyl, andC₆₋₁₀-aryl-C₂₋₆-alkynyl, wherein R^(BX) is C₁₋₆-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl,—C(O)-heteroaryl, C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl, whereinR^(BY) is hydrogen, C₁₋₆-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₁₋₁₀-haloalkyl, —C(O)—C₁₋₁₀-alkyl, —C(O)—C₆₋₁₀-aryl, —C(O)-heteroaryl,C₆₋₁₀-aryl, or 5- to 10-membered heteroaryl; and R^(DZ) is hydrogen oran oxygen protecting group; and treatment of the compound of Formula Fiwith an acid in an organic solvent.
 3. The method of claim 1, whereinstep (c) comprises an intramolecular Friedel-Crafts alkylation reaction.4. The method of claim 1, wherein the compound of Formula (Ci) is formedby reacting a compound of Formula (Ai) with a compound of Formula (Bi)or a compound of Formula (A′i) with a compound of Formula (B′i):

wherein LG is a leaving group; X is a halogen or pseudohalogen; and M isa metal.
 5. The method of claim 1, wherein each R^(M) is C₁₋₆-alkyl. 6.The method of claim 1, wherein LG is selected from the group consistingof halogen; —O—Ar¹ wherein Ar¹ is a substituted or unsubstitutedC₆₋₁₀-aryl or 5- to 10-membered heteroaryl; and —OSO₂R^(1a), whereinR^(1a) is aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl,—N(alkyl)₂, fluoro, or imidazolyl.
 7. The method of claim 2, wherein theacid is selected from the group consisting of TiCl₄, SnCl₄, and BF₃OEt₂.8. The method of claim 2, wherein the organic solvent is selected fromthe group consisting of dichloromethane, chlorobenzene,ethylenechloride, 1,2-dichlorobenzene, nitromethane, tetrachlorethane,and mixtures thereof.
 9. The method of claim 2, wherein X¹ or X² ishalogen.
 10. The method of claim 2, wherein X¹ and X² are both halogen.11. The method of claim 2, wherein R^(DZ) is selected from the groupconsisting of methyl, tert-butyloxycarbonyl (BOC), methoxymethyl (MOM),tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), andtribenzylsilyl.
 12. The method of claim 1, wherein the tetracycliccompound is


13. The method of claim 1, wherein the tetracyclic compound is selectedfrom the group consisting of:


14. The method of claim 1, wherein the compound of Formula (Di) isselected from the group consisting of:


15. The method of claim 2, wherein the compound of Formula (Ei) isselected from the group consisting of:


16. The method of claim 2, wherein X¹ or X² is halogen and R^(DZ) is anoxygen protecting group.
 17. The method of claim 16, wherein the oxygenprotecting group is selected from the group consisting of methyl,tert-butyloxycarbonyl (BOC), methoxymethyl (MOM),tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), andtribenzylsilyl.
 18. The method of claim 2, wherein X¹ or X² is halogen,R^(DZ) is an oxygen protecting group, Cy is a C₆₋₁₀-aryl or a 5- to10-membered heteroaryl, R¹³ is C₁₋₆-alkyl and each R¹⁷ is hydrogen. 19.The method of claim 2, wherein X¹ or X² is halogen and R^(DZ) is anoxygen protecting group and the acid is selected from the groupconsisting of TiCl₄, SnCl₄, and BF₃OEt₂.
 20. The method of claim 2,wherein X¹ or X² is halogen and R^(DZ) is an oxygen protecting group andthe organic solvent is selected from the group consisting ofdichloromethane, chlorobenzene, ethylenechloride, 1,2-dichlorobenzene,nitromethane, tetrachlorethane, and mixtures thereof.